Triazole compounds that modulate HSP90 activity

ABSTRACT

The present invention relates to substituted triazole compounds and compositions comprising substituted triazole compounds. The invention further relates to methods of treating or inhibiting angiogenesis in a subject in need thereof and methods for blocking, occluding, or otherwise disrupting blood flow in neo vasculature, in a subject in need thereof comprising administering to the subject a substituted triazole compound of the invention, or a composition comprising such a compound.

RELATED APPLICATIONS

This application is the U.S. National Stage of International ApplicationNo. PCT/US2007/017996, filed Aug. 14, 2007, published in English, andclaims the benefit of U.S. Provisional Application No. 60/838,306, filedAug. 17, 2006, the entire teachings of which are incorporated herein byreference.

BACKGROUND OF THE INVENTION

Heat shock proteins (HSPs) are a class of chaperone proteins that areup-regulated in response to elevated temperature and other environmentalstresses, such as ultraviolet light, nutrient deprivation, and oxygendeprivation. HSPs act as chaperones to other cellular proteins (calledclient proteins) and facilitate their proper folding and repair, and aidin the refolding of misfolded client proteins. There are several knownfamilies of HSPs, each having its own set of client proteins. The Hsp90family is one of the most abundant HSP families, accounting for about1-2% of proteins in a cell that is not under stress and increasing toabout 4-6% in a cell under stress. Inhibition of Hsp90 results indegradation of its client proteins via the ubiquitin proteasome pathway.Unlike other chaperone proteins, the client proteins of Hsp90 are mostlyprotein kinases or transcription factors involved in signaltransduction, and a number of its client proteins have been shown to beinvolved in the progression of cancer.

Hsp90 has been shown by mutational analysis to be necessary for thesurvival of normal eukaryotic cells. However, Hsp90 is over expressed inmany tumor types indicating that it may play a significant role in thesurvival of cancer cells and that cancer cells may be more sensitive toinhibition of Hsp90 than normal cells. For example, cancer cellstypically have a large number of mutated and overexpressed oncoproteinsthat are dependent on Hsp90 for folding. In addition, because theenvironment of a tumor is typically hostile due to hypoxia, nutrientdeprivation, acidosis, etc., tumor cells may be especially dependent onHsp90 for survival. Moreover, inhibition of Hsp90 causes simultaneousinhibition of a number of oncoproteins, as well as hormone receptors andtranscription factors making it an attractive target for an anti-canceragent. In fact, benzoquinone ansamycins, a family of natural productsthat inhibit Hsp90, has shown evidence of therapeutic activity inclinical trials.

Angiogenesis is a fundamental process of generating new blood vessels(neovasculature) in tissues or organs. Although angiogenesis isnecessary for organ growth and repair, uncontrolled angiogenesis isinvolved with or associated with many diseases or disorders. (e.g.cancers, macular degeneration, autoimmune diseases, etc.) As such,angiogenesis has become a target for the treatment of these diseases.Ferrara, N., et al., Nature 438:15 967-974 (2005).

Angiogenesis is controlled by a number of growth factors andcell-adhesion molecules in endothelial and mural cells. Ferrara, N., etal., Nature 438:15 967-974 (2005). Among these, VEGF-A (vascularendothelial growth factor-A) and its receptors have been widely studiedand characterized. Ferrara, N., et al., Nature 438:15 967-974 (2005). Itis believed that Hsp90 chaperones a number of proteins in the angiogeniccascade. Sanderson, S., et al., Mol Cancer Ther 5(3) 522-32 (2006). Datahas shown that VEGFR-2 (VEGF receptor) and other VEGFRs are Hsp90 clientproteins. Sanderson, S., et al., Mol Cancer Ther 5(3) 522-32 (2006).

A number of VEGF inhibitors are approved or currently in clinicaltrials. Carmeliet, P., Nature 438:15 932-936 (2005). Clinical trialshave shown that the current angiogenesis therapies have a number oflimitations, including being ineffective as a monotherapy andanti-angiogenic resistance. Carmeliet, Nature 438:15 932-936 (2005).Therefore, a need exists for new therapeutics that reduce or overcomethe limitations of currently used anti-angiogenic agents.

SUMMARY OF THE INVENTION

The present invention provides methods of treating or inhibiting (e.g.,reducing) angiogenesis. The present invention also provides methods forreducing, blocking, occluding, or otherwise disrupting blood flow inneovasculature. The present invention also provides new uses forpreviously disclosed compounds.

Triazole compounds that modulate Hsp90 activity have previously beendescribed in copending U.S. Publication No. 20060167070, filed Nov. 17,2005, which is incorporated by reference herein in its entirety.

The present invention provides compounds having the formula (I):

and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs thereof. In formula (I), ring A is an aryl or a heteroaryl,wherein the aryl or the heteroaryl are optionally further substitutedwith one or more substituents in addition to R₃;

R₁ is —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,—O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,—S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —OP(O)(OR₇)₂, or —SP(O)(OR₇)₂;

R₃ is —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,—O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,—S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)O₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —OP(O)(OR₇)₂, or —SP(O)(OR₇)₂;

R₅ is an optionally substituted heteroaryl or an optionally substituted8 to 14 membered aryl;

R₇ and R₈, for each occurrence, are, independently, —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl;

R₁₀ and R₁₁, for each occurrence, are independently —H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; or R₁₀ and R₁₁, taken together with the nitrogen to whichthey are attached, form an optionally substituted heterocyclyl or anoptionally substituted heteroaryl;

R₂₆ is a lower alkyl;

p, for each occurrence, is, independently, 1 or 2; and

m, for each occurrence, is independently, 1, 2, 3, or 4.

In one embodiment, ring A of the the compounds of formula (I) is not asubstituted [1,2,3]triazole, and/or compounds represented by formula (I)do not include3-(2,4-dihydroxy-phenyl)-4-(7-naphthalen-1-yl)-5-mercapto-triazole.

The present invention also provides compounds having the formula (II):

and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs thereof. In formula (II), ring A, R₁, and R₃ are defined asfor formula (I); and

R₂ is a substituted phenyl, wherein the phenyl group is substitutedwith:

-   -   i) one substituent selected from nitro, cyano, a haloalkoxy, an        optionally substituted alkenyl, an optionally substituted        alkynyl, an optionally substituted cycloalkyl, an optionally        substituted cycloalkenyl, an optionally substituted        heterocyclyl, an optionally substituted aryl, an optionally        substituted heteroaryl, an optionally substituted aralkyl, an        optionally substituted heteraralkyl, hydroxylalkyl, alkoxyalkyl,        guanadino, —NR₁₀R₁₁, —O—R₂₀, —C(O)R₇, —C(O)OR₂₀, —OC(O)R₇,        —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,        —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁, or    -   ii) two to five substituents selected from the group consisting        of an optionally substituted alkyl, an optionally substituted        alkenyl, an optionally substituted alkynyl, an optionally        substituted cycloalkyl, an optionally substituted cycloalkenyl,        an optionally substituted heterocyclyl, an optionally        substituted aryl, an optionally substituted heteroaryl, an        optionally substituted aralkyl, an optionally substituted        heteraralkyl, hydroxyalkyl, alkoxyalkyl, —F, —Br, —I, cyano,        nitro, guanadino, a haloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇,        —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇,        —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or        —S(O)_(p)NR₁₀R₁₁; and

R₂₀, for each occurrence, is independently an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl.

In one embodiment, compounds represented by formula (II) do not include3-(2,4-dihydroxy-phenyl)-4-(7-naphthalen-1-yl)-5-mercapto-triazole,3-(2,4-dihydroxyphenyl)-4-(2,5-dimethoxyphenyl)-5-mercapto-triazole,3-(1-phenyl-5-amino-pyrazol-4-yl)-4-(2,4-dichloropheny)-5-mercapto-triazole,or 3-(2-hydroxy-phenyl)-4-(2,4-dimethylphenyl)-5-mercapto-triazole.

The present invention also provides compounds having the formula (III):

and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs thereof. In formula (III), ring A, R₁, and R₃ are definedas for formula (I); and

R₁₈ is an optionally substituted cycloalkyl, and optionally substitutedcycloalkenyl, or a substituted alkyl, wherein the alkyl group issubstituted with one or more substituents independently selected fromthe group consisting of an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, halo, cyano, nitro, guanadino, ahaloalkyl, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂;

In one embodiment, compounds represented by formula (III) do not includecompounds in which R₁₈ is not cyclohexyl.

The invention also provides compounds represented by formula (IV) orformula (V):

and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs thereof. In formulas (IV) and (V), R₁ and R₃ are defined asfor formula (I); and

X₁₄ is O, S, or NR₇;

R₂₁ is an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, or anoptionally substituted heteraralkyl;

R₂₂, for each occurrence, is independently —H or is selected from thegroup consisting of an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl, a haloalkyl, —C(O)R₇, —C(O)OR₇,—OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —S(O)_(p)R₇, —S(O)_(p)OR₇, or—S(O)_(p)NR₁₀R₁₁; and

R₂₃ and R₂₄, for each occurrence, are independently —H or are selectedfrom the group consisting of an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇,—C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇,—S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or—S(O)_(p)NR₁₀R₁₁.

The present invention also provides compounds represented by formula(VI):

and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs thereof, wherein:

X₄₁ is O, S, or NR₄₂;

X₄₂ is CR₄₄ or N;

Y₄₀ is N or CR₄₃;

Y₄₁ is N or CR₄₅;

Y₄₂, for each occurrence, is independently N, C or CR₄₆;

Z is OH, SH, or NHR₇;

R₄₁ is —H, —OH, —SH, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, halo, cyano, nitro, guanadino, ahaloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy,—NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇, —C(S)SR₇,—C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂;

R₄₂ is —H, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, aheteroalkyl, —C(O)R₇, —(CH₂)_(m)C(O)OR₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —S(O)_(p)R₇, —S(O)_(p)OR₇, or —S(O)_(p)NR₁₀R₁₁;

R₄₃ and R₄₄ are, independently, —H, —OH, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl,hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, aheteroalkyl, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇,—S(O)_(p)NR₁₀R₁₁, or R₄₃ and R₄₄ taken together with the carbon atoms towhich they are attached form an optionally substituted cycloalkenyl, anoptionally substituted aryl, an optionally substituted heterocyclyl, oran optionally substituted heteroaryl;

R₄₅ is —H, —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,—O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,—S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁,—SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇,—NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇,—NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇,—OC(NR₈)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁, or —NR₇C(NR₈)N₁₀R₁₁;

R₄₆, for each occurrence, is independently selected from the groupconsisting of H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, halo, cyano, nitro, guanadino, ahaloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁;

R₇, R₈, R₁₀, R₁₁, R₂₆, p, and m are defined as above.

The present invention also provides compounds represented by formula(VII):

and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs, wherein:

Z₁ is —OH or —SH; and

X₄₂, R₄₁, R₄₂, R₄₃, and R₄₅ are defined as above.

The present invention also provides compounds having the formula (VIII):

and tautomers, pharmaceutically acceptable salts, solvtes, clathrates,and prodrugs thereof, wherein:

X₄₅ is CR₅₄ or N;

Z₁ is —OH or —SH;

R₅₂ is selected from the group consisting of —H, methyl, ethyl,n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, —(CH₂)₂OCH₃,—CH₂C(O)OH, and —C(O)N(CH₃)₂;

R₅₃ and R₅₄ are each, independently, —H, methyl, ethyl, or isopropyl; orR₅₃ and R₅₄ taken together with the carbon atoms to which they areattached form a phenyl, cyclohexenyl, or cyclooctenyl ring;

R₅₅ is selected from the group consisting of —H, —OH, —OCH₃, and—OCH₂CH₃; and

R₅₆ is selected from the group consisting of —H, methyl, ethyl,isopropyl, and cyclopropyl.

The present invention also provides compounds having the formula (IX):

and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs thereof, wherein,

X₄₄, for each occurrence, is independently, O, S, NR₄₂ or C(R₄₆)₂;

Y₄₃ is NR₄₂, C(R₄₆)₂, C(R₄₆)₂—C(R₄₆)₂, C(O), C(S), C(R₄₆)₂C(O), orC(R₄₆)₂C(S);

Y₄₁, Y₄₂, Z, R₄₁, R₄₂, and R₄₆ are defined as above.

In one embodiment, in formula (IX), R₄₁ is selected from the groupconsisting of —H, lower alkyl, lower alkoxy, lower cycloalkyl, and lowercycloalkoxy.

In another embodiment, in formula (IX), R₄₁ is selected from the groupconsisting of —H, methyl, ethyl, propyl, isopropyl, cyclopropyl,methoxy, ethoxy, propoxy, and cyclopropoxy.

In another embodiment, in formula (IX), R₄₂ is selected from the groupconsisting of —H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl,n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, —C(O)OH,—(CH₂)_(m)C(O)OH, —CH₂OCH₃, —CH₂CH₂OCH₃, and —C(O)N(CH₃)₂.

In another embodiment, in formula (IX), Y₄₁ is CR₄₅. Preferably, R₄₅ isH, a lower alkoxy, or —OH.

In another embodiment, in formula (IX), Y₄₂ is CH.

In another embodiment, in formula (IX), Y₄₃ is CH₂.

In another embodiment, in formula (IX), Y₄₃ is NR₄₂, wherein R₄₂ is H ora lower alkyl.

In another embodiment, in formula (IX), one of X₄₄ is NR₄₂ and the otheris CH₂ or C(R₆)₂. Preferably, one of X₄₄ is NR₄₂ and the other is CH₂.

In another embodiment, in formula (VI), Z is —OH.

In another embodiment, Z is —SH.

In another embodiment, the compound is selected from the groupconsisting of:

3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1,3-benzodiaxol-5-yl)-5-mercapto-[1,2,4]triazole;

3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(indan-5-yl)-5-mercapto-[1,2,4]triazole;

4-Ethyl-6-[5-mercapto-4-(1-methyl-2,3-dihydro-1H-indol-5-yl)-4H-[1,2,4]triazol-3-yl]-benzene-1,3-diol;

5-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-mercapto-4H-1,2,4-triazol-4-yl)indolin-2-one;

5-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-mercapto-4H-1,2,4-triazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one;

5-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-mercapto-4H-1,2,4-triazol-4-yl)-1-methylindolin-2-one;

4-isopropyl-6-(5-mercapto-4-(4-propyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-4H-1,2,4-triazol-3-yl)benzene-1,3-diol;

6-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-mercapto-4H-1,2,4-triazol-4-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one;

6-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-mercapto-4H-1,2,4-triazol-4-yl)-3-methylbenzo[d]thiazol-2(3H)-one;

6-(3-(5-ethyl-2,4-dihydroxyphenyl)-5-mercapto-4H-1,2,4-triazol-4-yl)benzo[d]thiazol-2(3H)-one;and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs thereof.

The present invention also provides compounds having the formula (X):

and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs thereof, wherein:

X₄₁, Y₄₁, Y₄₂, Z, R₇, R₈, R₁₀, R₁₁, R₄₁, R₄₆ and p are defined as above.

The compounds shown in Table 1 or compounds of any formula herein, ortautomers, pharmaceutically acceptable salts, solvates, clathrates,hydrates, polymorphs or prodrugs thereof, inhibit the activity of Hsp90and, thereby facilitates the degradation of Hsp90 client proteins. Hsp90is necessary for the survival of normal eukaryotic cells. The compoundsshown in Table 1 or compounds of any formula herein, or tautomers,pharmaceutically acceptable salts, solvates, clathrates, hydrates,polymorphs or prodrugs thereof, are useful for treating, reducing orinhibiting angiogenesis. The compounds shown in Table 1 or compounds ofany formula herein, or tautomers, pharmaceutically acceptable salts,solvates, clathrates, hydrates, polymorphs or prodrugs are also usefulfor reducing, blocking, occluding, or otherwise disrupting blood flow inneovasculature.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other objects, features and advantages of theinvention will be apparent from the following more particulardescription of preferred embodiments of the invention, as illustrated inthe accompanying drawings in which like reference characters refer tothe same parts throughout the different views. The drawings are notnecessarily to scale, emphasis instead being placed upon illustratingthe principles of the invention.

FIG. 1 is an image of the effect of Compound 226 on HUVEC migration atdifferent points in time (0, 24, 48, 72, and 106 hours) and at twoconcentrations (100 nM and 1 μM) in comparison to DMSO treated cells.

FIG. 2 is a quantification of the effect of Compound 226 on HUVECmigration shown if FIG. 1.

FIG. 3 is a larger magnification of FIG. 1 showing the effect ofCompound 226 on HUVEC migration.

FIG. 4 is an image showing the effect of Compound 226 (100 nM) on HUVECcell morphology (76 hours after treatment) at 2× and 20× magnificationcompared to DMSO treated cells.

FIG. 5 is an image showing the effect of Compound 226 (10 nM, 100 nM,and 1 μM) on VE-cadherin junction between HUVEC cells in comparison toDMSO treated cells.

DETAILED DESCRIPTION OF THE INVENTION

A description of preferred embodiments of the invention follows.

The present invention provides compounds and uses of said compounds. Thepresent invention encompasses the use of the compounds of the inventionto treat or inhibit (e.g., reduce) angiogenesis. The present inventionalso provides methods for reducing, blocking, occluding, or otherwisedisrupting blood flow in neovasculature.

In certain embodiments, the compounds of the invention can be used incombination with other therapies. In one aspect, compounds of theinvention can be used in combination with other anti-angiogenic agents.

A. Terminology

Unless otherwise specified, the below terms used herein are defined asfollows:

As used herein, the term “alkyl” means a saturated straight chain orbranched non-cyclic hydrocarbon having from 1 to 10 carbon atoms.Representative saturated straight chain alkyls include methyl, ethyl,n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl andn-decyl; while saturated branched alkyls include isopropyl, sec-butyl,isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl,3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl,2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl,2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl,2,2-dimethylhexyl, 3,3-dimethylpentyl, 3,3-dimethylhexyl,4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl,3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl,2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl,2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl,3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl and the like. Theterm “(C₁-C₆)alkyl” means a saturated straight chain or branchednon-cyclic hydrocarbon having from 1 to 6 carbon atoms. Representative(C₁-C₆)alkyl groups are those shown above having from 1 to 6 carbonatoms. Alkyl groups included in compounds of this invention may beoptionally substituted with one or more substituents.

As used herein, the term “alkenyl” means a saturated straight chain orbranched non-cyclic hydrocarbon, having from 2 to 10 carbon atoms andhaving at least one carbon-carbon double bond. Representative straightchain and branched (C₂-C₁₀)alkenyls include vinyl, allyl, 1-butenyl,2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl,2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl,3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl,3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl,3-decenyl and the like. Alkenyl groups may be optionally substitutedwith one or more substituents.

As used herein, the term “alkynyl” means a saturated straight chain orbranched non-cyclic hydrocarbon having from 2 to 10 carbon atoms andhaving at lease one carbon-carbon triple bond. Representative straightchain and branched alkynyls include acetylenyl, propynyl, 1-butynyl,2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 4-pentynyl,1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl,1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 8-nonynyl,1-decynyl, 2-decynyl, 9-decynyl, and the like. Alkynyl groups may beoptionally substituted with one or more substituents.

As used herein, the term “cycloalkyl” means a saturated, mono- orpolycyclic alkyl radical having from 3 to 20 carbon atoms.Representative cycloalkyls include cyclopropyl, 1-methylcyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, -cyclodecyl, octahydro-pentalenyl, and the like. Cycloalkylgroups may be optionally substituted with one or more substituents.

As used herein, the term “cycloalkenyl” means a mono- or poly-cyclicnon-aromatic alkyl radical having at least one carbon-carbon double bondin the cyclic system and from 3 to 20 carbon atoms. Representativecycloalkenyls include cyclopentenyl, cyclopentadienyl, cyclohexenyl,cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cycloheptatrienyl,cyclooctenyl, cyclooctadienyl, cyclooctatrienyl, cyclooctatetraenyl,cyclononenyl, cyclononadienyl, cyclodecenyl, cyclodecadienyl,1,2,3,4,5,8-hexahydronaphthalenyl and the like. Cycloalkenyl groups maybe optionally substituted with one or more substituents.

As used herein, the term “haloalkyl” means and alkyl group in which oneor more (including all) the hydrogen radicals are replaced by a halogroup, wherein each halo group is independently selected from —F, —Cl,—Br, and —I. The term “halomethyl” means a methyl in which one to threehydrogen radical(s) have been replaced by a halo group. Representativehaloalkyl groups include trifluoromethyl, bromomethyl,1,2-dichloroethyl, 4-iodobutyl, 2-fluoropentyl, and the like.

As used herein, an “alkoxy” is an alkyl group which is attached toanother moiety via an oxygen linker.

As used herein, an “haloalkoxy” is an haloalkyl group which is attachedto another moiety via an oxygen linker.

As used herein, the term an “aromatic ring” or “aryl” means ahydrocarbon monocyclic or polycyclic radical in which at least one ringis aromatic. Examples of suitable aryl groups include, but are notlimited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl,and naphthyl, as well as benzo-fused carbocyclic moieties such as5,6,7,8-tetrahydronaphthyl. Aryl groups may be optionally substitutedwith one or more substituents. In one embodiment, the aryl group is amonocyclic ring, wherein the ring comprises 6 carbon atoms, referred toherein as “(C₆)aryl.”

As used herein, the term “aralkyl” means an aryl group that is attachedto another group by a (C₁-C₆)alkylene group. Representative aralkylgroups include benzyl, 2-phenyl-ethyl, naphth-3-yl-methyl and the like.Aralkyl groups may be optionally substituted with one or moresubstituents.

As used herein, the term “alkylene” refers to an alkyl group that hastwo points of attachment. The term “(C₁-C₆)alkylene” refers to analkylene group that has from one to six carbon atoms. Straight chain(C₁-C₆)alkylene groups are preferred. Non-limiting examples of alkylenegroups include methylene (—CH₂—), ethylene (—CH₂CH₂—), n-propylene(—CH₂CH₂CH₂—), isopropylene (—CH₂CH(CH₃)—), and the like. Alkylenegroups may be optionally substituted with one or more substituents.

As used herein, the term “heterocyclyl” means a monocyclic (typicallyhaving 3- to 10-members) or a polycyclic (typically having 7- to20-members) heterocyclic ring system which is either a saturated ring ora unsaturated non-aromatic ring. A 3- to 10-membered heterocycle cancontain up to 5 heteroatoms; and a 7- to 20-membered heterocycle cancontain up to 7 heteroatoms. Typically, a heterocycle has at least oncarbon atom ring member. Each heteroatom is independently selected fromnitrogen, which can be oxidized (e.g., N(O)) or quaternized; oxygen; andsulfur, including sulfoxide and sulfone. The heterocycle may be attachedvia any heteroatom or carbon atom. Representative heterocycles includemorpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl,piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl,tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, andthe like. A heteroatom may be substituted with a protecting group knownto those of ordinary skill in the art, for example, the hydrogen on anitrogen may be substituted with a tert-butoxycarbonyl group.Furthermore, the heterocyclyl may be optionally substituted with one ormore substituents. Only stable isomers of such substituted heterocyclicgroups are contemplated in this definition.

As used herein, the term “heteroaromatic”, “heteroaryl” or like termsmeans a monocyclic or polycyclic heteroaromatic ring comprising carbonatom ring members and one or more heteroatom ring members. Eachheteroatom is independently selected from nitrogen, which can beoxidized (e.g., N(O)) or quaternized; oxygen; and sulfur, includingsulfoxide and sulfone. Representative heteroaryl groups include pyridyl,1-oxo-pyridyl, furanyl, benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, thienyl,pyrrolyl, oxazolyl, imidazolyl, thiazolyl, a isoxazolyl, quinolinyl,pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, atriazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl,benzoxazolyl, benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl,benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl,indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl,purinyl, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl,imidazo[1,2-a]pyridyl, and benzothienyl. In one embodiment, theheteroaromatic ring is selected from 5-8 membered monocyclic heteroarylrings. The point of attachment of a heteroaromatic or heteroaryl ring toanother group may be at either a carbon atom or a heteroatom of theheteroaromatic or heteroaryl rings. Heteroaryl groups may be optionallysubstituted with one or more substituents.

As used herein, the term “(C₅)heteroaryl” means an aromatic heterocyclicring of 5 members, wherein at least one carbon atom of the ring isreplaced with a heteroatom such as, for example, oxygen, sulfur ornitrogen. Representative (C₅)heteroaryls include furanyl, thienyl,pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl,isothiazolyl, pyrazinyl, triazolyl, thiadiazolyl, and the like.

As used herein, the term “(C₆)heteroaryl” means an aromatic heterocyclicring of 6 members, wherein at least one carbon atom of the ring isreplaced with a heteroatom such as, for example, oxygen, nitrogen orsulfur. Representative (C₆)heteroaryls include pyridyl, pyridazinyl,pyrazinyl, triazinyl, tetrazinyl and the like.

As used herein, the term “heteroaralkyl” means a heteroaryl group thatis attached to another group by a (C₁-C₆)alkylene. Representativeheteroaralkyls include 2-(pyridin-4-yl)-propyl, 2-(thien-3-yl)-ethyl,imidazol-4-yl-methyl and the like. Heteroaralkyl groups may beoptionally substituted with one or more substituents.

As used herein, the term “halogen” or “halo” means —F, —Cl, —Br or —I.

Suitable substituents for an alkyl, alkylene, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl, aryl, aralkyl, heteroaryl, andheteroaralkyl groups include any substituent which will form a stablecompound of the invention. Examples of substituents for an alkyl,alkylene, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl,aryl, aralkyl, heteroaryl, and heteroarylalkyl include an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,a haloalkyl, —C(O)NR₂₈R₂₉, —C(S)NR₂₈R₂₉, —C(NR₃₂)NR₂₈R₂₉, —NR₃₀C(O)R₃₁,—NR₃₀C(S)R₃₁, —NR₃₀C(NR₃₂)R₃₁, halo, —OR₃₀, cyano, nitro, haloalkoxy,—C(O)R₃₀, —C(S)R₃₀, —C(NR₃₂)R₃₀, —NR₂₈R₂₉, —C(O)OR₃₀, —C(S)OR₃₀,—C(NR₃₂)OR₃₀, —OC(O)R₃₀, —OC(S)R₃₀, —OC(NR₃₂)R₃₀, —NR₃₀C(O)NR₂₈R₂₉,—NR₃₀C(S)NR₂₈R₂₉, —NR₃₀C(NR₃₂)NR₂₈R₂₉, —OC(O)NR₂₈R₂₉, —OC(S)NR₂₈R₂₉,—OC(NR₃₂)NR₂₈R₂₉, —NR₃₀C(O)OR₃₁, —NR₃₀C(S)OR₃₁, —NR₃₀C(NR₃₂)OR₃₁,—S(O)_(h)R₃₀, —OS(O)_(p)R₃₀, —NR₃₀S(O)_(p)R₃₀, —S(O)_(p)NR₂₈R₂₉,—OS(O)_(p)NR₂₈R₂₉, or —NR₃₀S(O)_(p)NR₂₈R₂₉, wherein R₂₈ and R₂₉, foreach occurrence are, independently, H, an optionally substituted alkyl,an optionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl; or R₂₈and R₂₉ taken together with the nitrogen to which they are attached isoptionally substituted heterocyclyl or optionally substitutedheteroaryl;

R₃₀ and R₃₁ for each occurrence are, independently, H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, or an optionally substitutedheteraralkyl; and

R₃₂, for each occurrence is, independently, H, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, —C(O)R₃₀,—C(O)NR₂₈R₂₉, —S(O)_(p)R₃₀, or —S(O)_(p)NR₂₈R₂₉;

p, for each occurrence, is independently, 1 or 2; and

h is 0, 1 or 2.

In addition, alkyl, cycloalkyl, alkylene, a heterocyclyl, and anysaturated portion of a alkenyl, cycloalkenyl, alkynyl, aralkyl, andheteroaralkyl groups, may also be substituted with ═O, ═S, ═N—R₃₂.

When a heterocyclyl, heteroaryl, or heteroaralkyl group contains anitrogen atom, it may be substituted or unsubstituted. When a nitrogenatom in the aromatic ring of a heteroaryl group has a substituent thenitrogen may be a quaternary nitrogen.

As used herein, the terms “subject”, “patient” and “mammal” are usedinterchangeably. The terms “subject” and “patient” refer to an animal(e.g., a bird such as a chicken, quail or turkey, or a mammal),preferably a mammal including a non-primate (e.g., a cow, pig, horse,sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and a primate(e.g., a monkey, chimpanzee and a human), and more preferably a human.In one embodiment, the subject is a non-human animal such as a farmanimal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog, cat,guinea pig or rabbit). In a preferred embodiment, the subject is ahuman.

As used herein, the term “lower” refers to a group having up to fouratoms. For example, a “lower alkyl” refers to an alkyl radical havingfrom 1 to 4 carbon atoms, “lower alkoxy” refers to “—O—(C₁-C₄)alkyl anda “lower alkenyl” or “lower alkynyl” refers to an alkenyl or alkynylradical having from 2 to 4 carbon atoms, respectively.

Unless indicated otherwise, the compounds of the invention containingreactive functional groups (such as (without limitation) carboxy,hydroxy, thiol, and amino moieties) also include protected derivativesthereof. “Protected derivatives” are those compounds in which a reactivesite or sites are blocked with one ore more protecting groups. Examplesof suitable protecting groups for hydroxyl groups include benzyl,methoxymethyl, allyl, trimethylsilyl, tert-butyldimethylsilyl, acetate,and the like. Examples of suitable amine protecting groups includebenzyloxycarbonyl, tert-butoxycarbonyl, tert-butyl, benzyl andfluorenylmethyloxy-carbonyl (Fmoc). Examples of suitable thiolprotecting groups include benzyl, tert-butyl, acetyl, methoxymethyl andthe like. Other suitable protecting groups are well known to those ofordinary skill in the art and include those found in T. W. Greene,Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981.

As used herein, the term “compound(s) of this invention” and similarterms refers to a compound of formula (I), (II), (III), (IV), (V), (VI),(VII), (VIII), (IX), (X), or Table 1, or a pharmaceutically acceptablesalt, solvate, clathrate, hydrate, polymorph or prodrug thereof, andalso include protected derivatives thereof.

The compounds of the invention may contain one or more chiral centersand/or double bonds and, therefore, exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers, ordiastereomers. According to this invention, the chemical structuresdepicted herein, including the compounds of this invention, encompassall of the corresponding compounds' enantiomers, diastereomers andgeometric isomers, that is, both the stereochemically pure form (e.g.,geometrically pure, enantiomerically pure, or diastereomerically pure)and isomeric mixtures (e.g., enantiomeric, diastereomeric and geometricisomeric mixtures). In some cases, one enantiomer, diastereomer orgeometric isomer will possess superior activity or an improved toxicityor kinetic profile compared to other isomers. In those cases, suchenantiomers, diastereomers and geometric isomers of compounds of thisinvention are preferred.

As used herein, the term “polymorph” means solid crystalline forms of acompound of the present invention or complex thereof. Differentpolymorphs of the same compound can exhibit different physical, chemicaland/or spectroscopic properties. Different physical properties include,but are not limited to stability (e.g., to heat or light),compressibility and density (important in formulation and productmanufacturing), and dissolution rates (which can affectbioavailability). Differences in stability can result from changes inchemical reactivity (e.g., differential oxidation, such that a dosageform discolors more rapidly when comprised of one polymorph than whencomprised of another polymorph) or mechanical characteristics (e.g.,tablets crumble on storage as a kinetically favored polymorph convertsto thermodynamically more stable polymorph) or both (e.g., tablets ofone polymorph are more susceptible to breakdown at high humidity).Different physical properties of polymorphs can affect their processing.For example, one polymorph might be more likely to form solvates ormight be more difficult to filter or wash free of impurities thananother due to, for example, the shape or size distribution of particlesof it.

As used herein, the term “hydrate” means a compound of the presentinvention or a salt thereof, that further includes a stoichiometric ornon-stoichiometric amount of water bound by non-covalent intermolecularforces.

As used herein, he term “clathrate” means a compound of the presentinvention or a salt thereof in the form of a crystal lattice thatcontains spaces (e.g., channels) that have a guest molecule (e.g., asolvent or water) trapped within.

As used herein and unless otherwise indicated, the term “prodrug” meansa derivative of a compound that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide acompound of this invention. Prodrugs may become active upon suchreaction under biological conditions, or they may have activity in theirunreacted forms. Examples of prodrugs contemplated in this inventioninclude, but are not limited to, analogs or derivatives of compounds offormula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), orTable 1 that comprise biohydrolyzable moieties such as biohydrolyzableamides, biohydrolyzable esters, biohydrolyzable carbamates,biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzablephosphate analogues. Other examples of prodrugs include derivatives ofcompounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII),(IX), (X), or Table 1 that comprise —NO, —NO₂, —ONO, or —ONO₂ moieties.Prodrugs can typically be prepared using well-known methods, such asthose described by 1 BURGER'SMEDICINAL CHEMISTRY AND DRUG DISCOVERY(1995) 172-178, 949-982 (Manfred E. Wolff ed., 5^(th) ed).

As used herein and unless otherwise indicated, the terms“biohydrolyzable amide”, “biohydrolyzable ester”, “biohydrolyzablecarbamate”, “biohydrolyzable carbonate”, “biohydrolyzable ureide” and“biohydrolyzable phosphate analogue” mean an amide, ester, carbamate,carbonate, ureide, or phosphate analogue, respectively, that either: 1)does not destroy the biological activity of the compound and confersupon that compound advantageous properties in vivo, such as improvedwater solubility, improved circulating half-life in the blood (e.g.,because of reduced metabolism of the prodrug), improved uptake, improvedduration of action, or improved onset of action; or 2) is itselfbiologically inactive but is converted in vivo to a biologically activecompound. Examples of biohydrolyzable amides include, but are notlimited to, lower alkyl amides, α-amino acid amides, alkoxyacyl amides,and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable estersinclude, but are not limited to, lower alkyl esters, alkoxyacyloxyesters, alkyl acylamino alkyl esters, and choline esters. Examples ofbiohydrolyzable carbamates include, but are not limited to, loweralkylamines, substituted ethylenediamines, aminoacids,hydroxyalkylamines, heterocyclic and heteroaromatic amines, andpolyether amines.

As used herein, “Hsp90” includes each member of the family of heat shockproteins having a mass of about 90-kiloDaltons. For example, in humansthe highly conserved Hsp90 family includes cytosolic Hsp90α and Hsp90βisoforms, as well as GRP94, which is found in the endoplasmic reticulum,and HSP75/TRAP1, which is found in the mitochondrial matrix.

As used herein, a “proliferative disorder” or a “hyperproliferativedisorder,” and other equivalent terms, means a disease or medicalcondition involving pathological growth of cells. Proliferativedisorders include cancer, smooth muscle cell proliferation, systemicsclerosis, cirrhosis of the liver, adult respiratory distress syndrome,idiopathic cardiomyopathy, lupus erythematosus, retinopathy, e.g.,diabetic retinopathy or other retinopathies, cardiac hyperplasia,reproductive system associated disorders such as benign prostatichyperplasia and ovarian cysts, pulmonary fibrosis, endometriosis,fibromatosis, harmatomas, lymphangiomatosis, sarcoidosis, desmoidtumors,

Smooth muscle cell proliferation includes hyperproliferation of cells inthe vasculature, for example, intimal smooth muscle cell hyperplasia,restenosis and vascular occlusion, particularly stenosis followingbiologically- or mechanically-mediated vascular injury, e.g., vascularinjury associated with angioplasty. Moreover, intimal smooth muscle cellhyperplasia can include hyperplasia in smooth muscle other than thevasculature, e.g., bile duct blockage, bronchial airways of the lung inpatients with asthma, in the kidneys of patients with renal interstitialfibrosis, and the like.

Non-cancerous proliferative disorders also include hyperproliferation ofcells in the skin such as psoriasis and its varied clinical forms,Reiter's syndrome, pityriasis rubra pilaris, and hyperproliferativevariants of disorders of keratinization (e.g., actinic keratosis, senilekeratosis), scleroderma, and the like.

Cancers that can be treated or prevented by the methods of the presentinvention include, but are not limited to human sarcomas and carcinomas,e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenicsarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor,leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer,breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma,basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceousgland carcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testiculartumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma,epithelial carcinoma, glioma, astrocytoma, medulloblastoma,craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acousticneuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma,retinoblastoma; leukemias, e.g., acute lymphocytic leukemia and acutemyelocytic leukemia (myeloblastic, promyelocytic, myelomonocytic,monocytic and erythroleukemia); chronic leukemia (chronic myelocytic(granulocytic) leukemia and chronic lymphocytic leukemia); andpolycythemia vera, lymphoma (Hodgkin's disease and non-Hodgkin'sdisease), multiple myeloma, Waldenstrobm's macroglobulinemia, and heavychain disease.

Other examples of leukemias include acute and/or chronic leukemias,e.g., lymphocytic leukemia (e.g., as exemplified by the p388 (murine)cell line), large granular lymphocytic leukemia, and lymphoblasticleukemia; T-cell leukemias, e.g., T-cell leukemia (e.g., as exemplifiedby the CEM, Jurkat, and HSB-2 (acute), YAC-1 (murine) cell lines),T-lymphocytic leukemia, and T-lymphoblastic leukemia; B cell leukemia(e.g., as exemplified by the SB (acute) cell line), and B-lymphocyticleukemia; mixed cell leukemias, e.g., B and T cell leukemia and B and Tlymphocytic leukemia; myeloid leukemias, e.g., granulocytic leukemia,myelocytic leukemia (e.g., as exemplified by the HL-60 (promyelocyte)cell line), and myelogenous leukemia (e.g., as exemplified by theK562(chronic) cell line); neutrophilic leukemia; eosinophilic leukemia;monocytic leukemia (e.g., as exemplified by the THP-1 (acute) cellline); myelomonocytic leukemia; Naegeli-type myeloid leukemia; andnonlymphocytic leukemia. Other examples of leukemias are described inChapter 60 of The Chemotherapy Sourcebook, Michael C. Perry Ed.,Williams & Williams (1992) and Section 36 of Holland Frie CancerMedicine 5th Ed., Bast et al. Eds., B.C. Decker Inc. (2000). The entireteachings of the preceding references are incorporated herein byreference.

As used herein the term “multi-drug resistant cancer” refers to a cancerwhich initially responded to an anti-cancer drug becomes resistant tothe anti-cancer drug when the anti-cancer drug is no longer effective intreating the subject with the cancer. For example, many tumors willinitially respond to treatment with an anti-cancer drug by decreasing insize or even going into remission, only to develop resistance to thedrug. Drug resistant tumors are characterized by a resumption of theirgrowth and/or reappearance after having seemingly gone into remission,despite the administration of increased dosages of the anti-cancer drug.Cancers that have developed resistance to two or more anti-cancer drugsare said to be “multi-drug resistant”. For example, it is common forcancers to become resistant to three or more anti-cancer agents, oftenfive or more anti-cancer agents and at times ten or more anti-canceragents.

As used herein, the term “pharmaceutically acceptable salt,” is a saltformed from, for example, an acid and a basic group of one of thecompounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII),(IX), (X), or Table 1. Illustrative salts include, but are not limited,to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide,nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, besylate, gentisinate,fumarate, gluconate, glucaronate, saccharate, formate, benzoate,glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate, and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term“pharmaceutically acceptable salt” also refers to a salt prepared from acompound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII),(IX), (X), or Table 1 having an acidic functional group, such as acarboxylic acid functional group, and a pharmaceutically acceptableinorganic or organic base. Suitable bases include, but are not limitedto, hydroxides of alkali metals such as sodium, potassium, and lithium;hydroxides of alkaline earth metal such as calcium and magnesium;hydroxides of other metals, such as aluminum and zinc; ammonia, andorganic amines, such as unsubstituted or hydroxy-substituted mono-, di-,or trialkylamines; dicyclohexylamine; tributyl amine; pyridine;N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, ortris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, ortris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, ortris-(hydroxymethyl)methylamine, N,N,-di-lower alkyl-N-(hydroxy loweralkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, ortri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such asarginine, lysine, and the like. The term “pharmaceutically acceptablesalt” also refers to a salt prepared from a compound of formula (I),(II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or Table 1having a basic functional group, such as an amine functional group, anda pharmaceutically acceptable inorganic or organic acid. Suitable acidsinclude, but are not limited to, hydrogen sulfate, citric acid, aceticacid, oxalic acid, hydrochloric acid (HCl), hydrogen bromide (HBr),hydrogen iodide (HI), nitric acid, hydrogen bisulfide, phosphoric acid,lactic acid, salicylic acid, tartaric acid, bitartratic acid, ascorbicacid, succinic acid, maleic acid, besylic acid, fumaric acid, gluconicacid, glucaronic acid, formic acid, benzoic acid, glutamic acid,methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, andp-toluenesulfonic acid.

In one embodiment, compounds of the invention are vascular targetingagents. In one aspect, compounds of the invention are effective forreducing, blocking, occluding, or otherwise disrupting blood flow in“neovasculature.” In one aspect, the invention provides a noveltreatment for diseases involving the growth of new blood vessels(“neovasculature”), including, but not limited to: cancer; infectiousdiseases; autoimmune disorders; benign tumors, e.g. hemangiomas,acoustic neuromas, neurofibromas, trachomas, and pyogenic granulomas;artheroscleric plaques; ocular angiogenic diseases, e.g., diabeticretinopathy, retinopathy of prematurity, macular degeneration, cornealgraft rejection, neovascular glaucoma, retrolental fibroplasia,rubeosis, retinoblastoma, persistent hyperplastic vitreous syndrome,choroidal neovascularization, uvietis and Pterygia (abnormal bloodvessel growth) of the eye; rheumatoid arthritis; psoriasis; warts;allergic dermatitis; blistering disease; Karposi sarcoma; delayed woundhealing; endometriosis; uterine bleeding; ovarian cysts; ovarianhyperstimulation; vasculogenesis; granulations; hypertrophic scars(keloids); nonunion fractures; scleroderma; trachoma; vascularadhesions; vascular malformations; DiGeorge syndrome; HHT; transplantarteriopathy; restinosis; obesity; myocardial angiogenesis; coronarycollaterals; cerebral collaterals; arteriovenous malformations; ischemiclimb angiogenesis; primary pulmonary hypertension; pulmonary edema;asthma; nasal polyps; inflammatory bowel disease; periodontal disease;ascites; peritoneal adhesions; Osler-Webber Syndrome; plaqueneovascularization; telangiectasia; hemophiliac joints; synovitis;osteomyelitis; osteophyte formation; angiofibroma; fibromusculardysplasia; wound granulation; Crohn's disease; and atherosclerosis.

Vascular targeting can be demonstrated by any method known to thoseskilled in the art, such as the method described herein in Examples 170and 171.

As used herein, the term “angiogenesis” refers to a fundamental processof generating new blood vessels in tissues or organs. Angiogenesis isinvolved with or associated with many diseases or conditions, including,but not limited to: cancer; ocular neovascular disease; age-relatedmacular degeneration; diabetic retinopathy, retinopathy of prematurity;corneal graft rejection; neovascular glaucoma; retrolental fibroplasias;epidemic keratoconjunctivitis; Vitamin A deficiency; contact lensoverwear; atopic keratitis; superior limbic keratitis; pterygiumkeratitis sicca; sjogrens; acne rosacea; warts; eczema; phylectenulosis;syphilis; Mycobacteria infections; lipid degeneration; chemical burns;bacterial ulcers; fungal ulcers; Herpes simplex infections; Herpeszoster infections; protozoan infections; Kaposi's sarcoma; Mooren'sulcer; Terrien's marginal degeneration; mariginal keratolysis;rheumatoid arthritis; systemic lupus; polyarteritis; trauma; Wegener'ssarcoidosis; scleritis; Stevens-Johnson disease; pemphigoid; radialkeratotomy; corneal graph rejection; diabetic retinopathy; maculardegeneration; sickle cell anemia; sarcoid; syphilis; pseudoxanthomaelasticum; Paget's disease; vein occlusion; artery occlusion; carotidobstructive disease; chronic uveitis/vitritis; mycobacterial infections;Lyme's disease; systemic lupus erythematosis; retinopathy ofprematurity; Eales' disease; Behcet's disease; infections causing aretinitis or choroiditis; presumed ocular histoplasmosis; Best'sdisease; myopia; optic pits; Stargardt's disease; pars planitis; chronicretinal detachment; hyperviscosity syndromes; toxoplasmosis; trauma andpost-laser complications; diseases associated with rubeosis(neovasculariation of the angle); diseases caused by the abnormalproliferation of fibrovascular or fibrous tissue including all forms ofproliferative vitreoretinopathy; rheumatoid arthritis; osteoarthritis;ulcerative colitis; Crohn's disease; Bartonellosis; atherosclerosis;Osler-Weber-Rendu disease; hereditary hemorrhagic telangiectasia;pulmonary hemangiomatosis; pre-eclampsia; endometriosis; fibrosis of theliver and of the kidney; developmental abnormalities (organogenesis);skin discolorations (e.g., hemangioma, nevus flammeus, or nevussimplex); wound healing; hypertrophic scars, i.e., keloids; woundgranulation; vascular adhesions; cat scratch disease (Rochele ninaliaquintosa); ulcers (Helicobacter pylori); keratoconjunctivitis;gingivitis; periodontal disease; epulis; hepatitis; tonsillitis;obesity; rhinitis; laryngitis; tracheitis; bronchitis; bronchiolitis;pneumonia; interstitial pulmonary fibrosis; pulmonary edema;neurodermitis; thyroiditis; thyroid enlargement; endometriosis;glomerulonephritis; gastritis; inflammatory bone and cartilagedestruction; thromboembolic disease; and Buerger's disease.

As used herein, the term “pharmaceutically acceptable solvate,” is asolvate formed from the association of one or more pharmaceuticallyacceptable solvent molecules to one of the compounds of formula (I),(II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or Table 1. Theterm solvate includes hydrates (e.g., hemihydrate, monohydrate,dihydrate, trihydrate, tetrahydrate, and the like).

A pharmaceutically acceptable carrier may contain inert ingredientswhich do not unduly inhibit the biological activity of the compounds.The pharmaceutically acceptable carriers should be biocompatible, i.e.,non-toxic, non-inflammatory, non-immunogenic and devoid of otherundesired reactions upon the administration to a subject. Standardpharmaceutical formulation techniques can be employed, such as thosedescribed in Remington's Pharmaceutical Sciences, ibid. Suitablepharmaceutical carriers for parenteral administration include, forexample, sterile water, physiological saline, bacteriostatic saline(saline containing about 0.9% mg/ml benzyl alcohol), phosphate-bufferedsaline, Hank's solution, Ringer's-lactate and the like. Methods forencapsulating compositions (such as in a coating of hard gelatin orcyclodextran) are known in the art (Baker, et al., “Controlled Releaseof Biological Active Agents”, John Wiley and Sons, 1986).

As used herein, the term “effective amount” refers to an amount of acompound of this invention which is sufficient to reduce or amelioratethe severity, duration, progression, or onset of an angiogenesis relateddisorder, prevent the advancement of a an angiogenesis related disorder,cause the regression of an angiogenesis related disorder, prevent therecurrence, development, onset or progression of a symptom associatedwith an angiogenesis related disorder, or enhance or improve theprophylactic or therapeutic effect(s) of another therapy. In oneembodiment, the term refers to the amount of the compound needed toreduce, block, occlude, or otherwise disrupt blood flow inneovasculature. The precise amount of compound administered to a subjectwill depend on the mode of administration, the type and severity of thedisease or condition and on the characteristics of the subject, such asgeneral health, age, sex, body weight and tolerance to drugs. It willalso depend on the degree, severity and type of the angiogenesisrelated, and the mode of administration. The skilled artisan will beable to determine appropriate dosages depending on these and otherfactors. When co-administered with other agents, e.g., whenco-administered with a chemotherapeutic agent, an “effective amount” ofthe second agent will depend on the type of drug used. Suitable dosagesare known for approved agents and can be adjusted by the skilled artisanaccording to the condition of the subject, the type of condition(s)being treated and the amount of a compound of the invention being used.In cases where no amount is expressly noted, an effective amount shouldbe assumed.

Non-limiting examples of an effective amount of a compound of theinvention are provided herein below. In a specific embodiment, theinvention provides a method of preventing, treating, managing, orameliorating an angiogenisis related disorder or one or more symptomsthereof, said methods comprising administering to a subject in needthereof a dose of at least 150 μg/kg, preferably at least 250 μg/kg, atleast 500 μg/kg, at least 1 mg/kg, at least 5 mg/kg, at least 10 mg/kg,at least 25 mg/kg, at least 50 mg/kg, at least 75 mg/kg, at least 100mg/kg, at least 125 mg/kg, at least 150 mg/kg, or at least 200 mg/kg ormore of one or more compounds of the invention once every day,preferably, once every 2 days, once every 3 days, once every 4 days,once every 5 days, once every 6 days, once every 7 days, once every 8days, once every 10 days, once every two weeks, once every three weeks,or once a month.

The dosages of a chemotherapeutic agents other than compounds of theinvention, which have been or are currently being used to prevent,treat, manage, or ameliorate a proliferative disorder, or one or moresymptoms thereof, can be used in the combination therapies of theinvention. Preferably, dosages lower than those which have been or arecurrently being used to prevent, treat, manage, or ameliorate aproliferative disorder, or one or more symptoms thereof, are used in thecombination therapies of the invention. The recommended dosages ofagents currently used for the prevention, treatment, management, oramelioration of a proliferative disorder, or one or more symptomsthereof, can obtained from any reference in the art including, but notlimited to, Hardman et al., eds., 1996, Goodman & Gilman's ThePharmacological Basis Of Basis Of Therapeutics 9^(th) Ed, Mc-Graw-Hill,New York; Physician's Desk Reference (PDR) 57^(th) Ed., 2003, MedicalEconomics Co., Inc., Montvale, N.J., which are incorporated herein byreference in its entirety.

As used herein, the terms “treat”, “treatment” and “treating” refer tothe reduction or amelioration of the progression, severity and/orduration of a disease or disorder, or the amelioration of one or moresymptoms (preferably, one or more discernible symptoms) of a disease ordisorder resulting from the administration of one or more therapies(e.g., one or more therapeutic agents such as a compound of theinvention). In specific embodiments, the terms “treat”, “treatment” and“treating” refer to the amelioration of at least one measurable physicalparameter of an angiogenesis related disorder, not necessarilydiscernible by the patient. In other embodiments the terms “treat”,“treatment” and “treating” refer to the inhibition (e.g., reduction) ofthe progression of an angiogenesis related disorder, either physicallyby, e.g., stabilization of a discernible symptom, physiologically by,e.g., stabilization of a physical parameter, or both. In otherembodiments the terms “treat”, “treatment” and “treating” refers toreduce, blocking, occluding, or otherwise disrupting blood flow inneovasculature.

As used herein, the terms “prevent”, “prevention” and “preventing” referto the reduction in the risk of acquiring or developing a disease ordisorder, or the reduction or inhibition of the recurrence or a diseaseor disorder. In one embodiment, a compound of the invention isadministered as a preventative measure to a patient, preferably a human,having a genetic predisposition to any of the disorders describedherein.

As used herein, the terms “therapeutic agent” and “therapeutic agents”refer to any agent(s) which can be used in the treatment, management, oramelioration of a disease or disorder or one or more symptoms thereof.In certain embodiments, the term “therapeutic agent” refers to acompound of the invention. In certain other embodiments, the term“therapeutic agent” refers does not refer to a compound of theinvention. Preferably, a therapeutic agent is an agent which is known tobe useful for, or has been or is currently being used for the treatment,management, prevention, or amelioration of an angiogenesis relateddisorder or one or more symptoms thereof.

As used herein, the term “synergistic” refers to a combination of acompound of the invention and another therapy (e.g., a prophylactic ortherapeutic agent), which is more effective than the additive effects ofthe therapies. A synergistic effect of a combination of therapies (e.g.,a combination of prophylactic or therapeutic agents) permits the use oflower dosages of one or more of the therapies and/or less frequentadministration of said therapies to a subject with a proliferativedisorder. The ability to utilize lower dosages of a therapy (e.g., aprophylactic or therapeutic agent) and/or to administer said therapyless frequently reduces the toxicity associated with the administrationof said therapy to a subject without reducing the efficacy of saidtherapy in the prevention, management or treatment of a proliferativedisorder. In addition, a synergistic effect can result in improvedefficacy of agents in the prevention, management or treatment of anangiogenesis related disorder. Finally, a synergistic effect of acombination of therapies (e.g., a combination of prophylactic ortherapeutic agents) may avoid or reduce adverse or unwanted side effectsassociated with the use of either therapy alone.

As used herein, the phrase “side effects” encompasses unwanted andadverse effects of a therapy (e.g., a prophylactic or therapeuticagent). Side effects are always unwanted, but unwanted effects are notnecessarily adverse. An adverse effect from a therapy (e.g.,prophylactic or therapeutic agent) might be harmful or uncomfortable orrisky. Side effects include, but are not limited to fever, chills,lethargy, gastrointestinal toxicities (including gastric and intestinalulcerations and erosions), nausea, vomiting, neurotoxicities,nephrotoxicities, renal toxicities (including such conditions aspapillary necrosis and chronic interstitial nephritis), hepatictoxicities (including elevated serum liver enzyme levels),myelotoxicities (including leukopenia, myelosuppression,thrombocytopenia and anemia), dry mouth, metallic taste, prolongation ofgestation, weakness, somnolence, pain (including muscle pain, bone painand headache), hair loss, asthenia, dizziness, extra-pyramidal symptoms,akathisia, cardiovascular disturbances and sexual dysfunction.

As used herein, the term “in combination” refers to the use of more thanone therapies (e.g., one or more prophylactic and/or therapeuticagents). The use of the term “in combination” does not restrict theorder in which therapies (e.g., prophylactic and/or therapeutic agents)are administered to a subject with a disease or disorder. A firsttherapy (e.g., a prophylactic or therapeutic agent such as a compound ofthe invention) can be administered prior to (e.g., 5 minutes, 15minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks,4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantlywith, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6weeks, 8 weeks, or 12 weeks after) the administration of a secondtherapy (e.g., a prophylactic or therapeutic agent such as ananti-cancer agent) to a subject with an angiogenesis related disorder,such as macular degeneration.

As used herein, the terms “therapies” and “therapy” can refer to anyprotocol(s), method(s), and/or agent(s) that can be used in theprevention, treatment, management, or amelioration of an angiogenesisrelated disorder or one or more symptoms thereof.

A used herein, a “protocol” includes dosing schedules and dosingregimens. The protocols herein are methods of use and includeprophylactic and therapeutic protocols.

As used herein, the terms “manage,” “managing,” and “management” referto the beneficial effects that a subject derives from a therapy (e.g., aprophylactic or therapeutic agent), which does not result in a cure ofthe disease. In certain embodiments, a subject is administered one ormore therapies (e.g., one or more prophylactic or therapeutic agents) to“manage” a disease so as to prevent the progression or worsening of thedisease.

As used herein, a composition that “substantially” comprises a compoundmeans that the composition contains more than about 80% by weight, morepreferably more than about 90% by weight, even more preferably more thanabout 95% by weight, and most preferably more than about 97% by weightof the compound.

As used herein, a reaction that is “substantially complete” means thatthe reaction contains more than about 80% by weight of the desiredproduct, more preferably more than about 90% by weight of the desiredproduct, even more preferably more than about 95% by weight of thedesired product, and most preferably more than about 97% by weight ofthe desired product.

As used herein, a racemic mixture means about 50% of one enantiomer andabout 50% of is corresponding enantiomer relative to a chiral center inthe molecule. The invention encompasses all enantiomerically-pure,enantiomerically-enriched, diastereomerically pure, diastereomericallyenriched, and racemic mixtures of the compounds of the invention.

Enantiomeric and diastereomeric mixtures can be resolved into theircomponent enantiomers or diastereomers by well known methods, such aschiral-phase gas chromatography, chiral-phase high performance liquidchromatography, crystallizing the compound as a chiral salt complex, orcrystallizing the compound in a chiral solvent. Enantiomers anddiastereomers can also be obtained from diastereomerically- orenantiomerically-pure intermediates, reagents, and catalysts by wellknown asymmetric synthetic methods.

The compounds of the invention are defined herein by their chemicalstructures and/or chemical names. Where a compound is referred to byboth a chemical structure and a chemical name, and the chemicalstructure and chemical name conflict, the chemical structure isdeterminative of the compound's identity.

When administered to a patient, e.g., to a non-human animal forveterinary use or for improvement of livestock, or to a human forclinical use, the compounds of the invention are administered inisolated form or as the isolated form in a pharmaceutical composition.As used herein, “isolated” means that the compounds of the invention areseparated from other components of (a) a natural source, such as a plantor cell, preferably bacterial culture, or (b) a synthetic organicchemical reaction mixture. Preferably, the compounds of the inventionare purified via conventional techniques. As used herein, “purified”means that when isolated, the isolate contains at least 95%, preferablyat least 98%, of a compound of the invention by weight of the isolateeither as a mixture of stereoisomers or as a diastereomeric orenantiomeric pure isolate.

As used herein, a composition that is “substantially free” of a compoundmeans that the composition contains less than about 20% by weight, morepreferably less than about 10% by weight, even more preferably less thanabout 5% by weight, and most preferably less than about 3% by weight ofthe compound.

Only those choices and combinations of substituents that result in astable structure are contemplated. Such choices and combinations will beapparent to those of ordinary skill in the art and may be determinedwithout undue experimentation.

The invention can be understood more fully by reference to the followingdetailed description and illustrative examples, which are intended toexemplify non-limiting embodiments of the invention.

B. The Compounds of the Invention

The present invention encompasses compounds having Formulas (I), (II),(III), (IV), (V), (VI), (VII), (VIII), (IX), (X), and those set forth inTable 1 and tautomers, pharmaceutically acceptable salts, solvates,clathrates, hydrates, polymorphs and prodrugs thereof. In one aspect,the invention provides compounds of formula (I) as set forth below:

and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs thereof, wherein ring A, R₁, R₃ and R₅ are defined asabove.

Compounds of formula (I) inhibit the activity of Hsp90 and areparticularly useful for treating or preventing (e.g., reduce thelikelihood of developing) angiogenesis related disorders, such asmacular degeneration. In addition, compounds of formula (I) areparticularly useful in reducing, blocking, occluding, or otherwisedisrupting blood flow in neovasculature.

In one embodiment, in the compounds of formula (I), R₅ is an optionallysubstituted naphthyl.

In another embodiment, in the compounds of formula (I), R₅ isrepresented by the following formula:

wherein:

R₉, for each occurrence, is independently a substituent selected fromthe group consisting of an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇,—C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇,—S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or—S(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇, —OP(O)(OR₇)₂, or —SP(O)(OR₇)₂;

or two R₉ groups taken together with the carbon atoms to which they areattached form a fused ring; and

m is zero or an integer from 1 to 7, wherein R₇, R₈, R₁₀, R₁₁, and p aredefined as above.

In another embodiment, in the compounds represented by formula (I), R₅is represented by one of the following formulas:

wherein R₉ is defined as above;

q is zero or an integer from 1 to 7; and

u is zero or an integer from 1 to 8.

In another embodiment, in the compounds represented by formula (I), R₅is selected from the group consisting of:

wherein:

X₆, for each occurrence, is independently CH, CR₉, N, N(O), N⁺(R₁₇),provided that at least three X₆ groups are independently selected fromCH and CR₉;

X₇, for each occurrence, is independently CH, CR₉, N, N(O), N⁺(R₁₇),provided that at least three X₇ groups are independently selected fromCH and CR₉;

X₈, for each occurrence, is independently CH₂, CHR₉, CR₉R₉, O, S, S(O)p,NR₇, or NR₁₇;

X₉, for each occurrence, is independently N or CH;

X₁₀, for each occurrence, is independently CH, CR₉, N, N(O), N⁺(R₁₇),provided that at least one X₁₀ is selected from CH and CR₉;

R₁₇, for each occurrence, is independently —H, an alkyl, an aralkyl,—C(O)R₇, —C(O)OR₇, or —C(O)NR₁₀R₁₁; wherein R₇, R₉, R₁₀, R₁₁ and p aredefined as above.

In another embodiment, in the compounds represented by formula (I), R₅is an optionally substituted indolyl, an optionally substitutedbenzoimidazolyl, an optionally substituted indazolyl, an optionallysubstituted 3H-indazolyl, an optionally substituted indolizinyl, anoptionally substituted quinolinyl, an optionally substitutedisoquinolinyl, an optionally substituted benzoxazolyl, an optionallysubstituted benzo[1,3]dioxolyl, an optionally substituted benzofuryl, anoptionally substituted benzothiazolyl, an optionally substitutedbenzo[d]isoxazolyl, an optionally substituted benzo[d]isothiazolyl, anoptionally substituted thiazolo[4,5-c]pyridinyl, an optionallysubstituted thiazolo[5,4-c]pyridinyl, an optionally substitutedthiazolo[4,5-b]pyridinyl, an optionally substitutedthiazolo[5,4-b]pyridinyl, an optionally substitutedoxazolo[4,5-c]pyridinyl, an optionally substitutedoxazolo[5,4-c]pyridinyl, an optionally substitutedoxazolo[4,5-b]pyridinyl, an optionally substitutedoxazolo[5,4-b]pyridinyl, an optionally substituted imidazopyridinyl, anoptionally substituted benzothiadiazolyl, benzoxadiazolyl, an optionallysubstituted benzotriazolyl, an optionally substituted tetrahydroindolyl,an optionally substituted azaindolyl, an optionally substitutedquinazolinyl, an optionally substituted purinyl, an optionallysubstituted imidazo[4,5-a]pyridinyl, an optionally substitutedimidazo[1,2-a]pyridinyl, an optionally substituted3H-imidazo[4,5-b]pyridinyl, an optionally substituted1H-imidazo[4,5-b]pyridinyl, an optionally substituted1H-imidazo[4,5-c]pyridinyl, an optionally substituted3H-imidazo[4,5-c]pyridinyl, an optionally substituted pyridopyrdazinyl,and optionally substituted pyridopyrimidinyl, an optionally substitutedpyrrolo[2,3]pyrimidyl, an optionally substituted pyrazolo[3,4]pyrimidylan optionally substituted cyclopentaimidazolyl, an optionallysubstituted cyclopentatriazolyl, an optionally substitutedpyrrolopyrazolyl, an optionally substituted pyrroloimidazolyl, anoptionally substituted pyrrolotriazolyl, or an optionally substitutedbenzo(b)thienyl.

In another embodiment, in the compounds represented by formula (I), R₅is an optionally substituted indolyl. Preferably, R₅ is an indolylrepresented by the following structural formula:

wherein:

R₃₃ is a halo, lower alkyl, a lower alkoxy, a lower haloalkyl, a lowerhaloalkoxy, and lower alkyl sulfanyl;

R₃₄ is H, a lower alkyl, or a lower alkylcarbonyl; and

Ring B and Ring C are optionally substituted with one or moresubstituents.

In another embodiment, in the compounds represented by formula (I), R₅is selected from the group consisting of:

wherein:

X₁₁, for each occurrence, is independently CH, CR₉, N, N(O), or N⁺(R₁₇),provided that at least one X₁₁ is N, N(O), or N⁺(R₁₇) and at least twoX₁₁ groups are independently selected from CH and CR₉;

X₁₂, for each occurrence, is independently CH, CR₉, N, N(O), N⁺(R₁₇),provided that at least one X₁₂ group is independently selected from CHand CR₉;

X₁₃, for each occurrence, is independently O, S, S(O)p, NR₇, or NR₁₇;wherein R₇, R₉ and R₁₇ are defined as above.

In another embodiment, in compounds represented by formula (I), or anyof the embodiments of formula (I) in which particular groups aredisclosed, the compound is represented by the following structuralformula:

wherein R₁, R₃, and R₅ are defined as above; and

R₆, for each occurrence, is independently an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteroaralkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy,—NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇, —C(S)SR₇,—C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇, —NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇ , —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S (O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂; and

n is zero of an integer from 1 to 4, wherein R₇, R₈, R₁₀, R₁₁, and p aredefined as above.

In another embodiment, in compounds represented by formula (I), or anyof the embodiments of formula (I) in which particular groups aredisclosed, the compound is represented by the following structuralformula:

wherein R₁, R₃, R₅, and R₆ are defined as above; and

R₂₅ is an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, aheteroalkyl, alkoxy, haloalkoxy, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇,—C(S)R₇, —C(O)SR₇, —C(S)SR₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇,—OC(NR₈)OR₇, —SC(O)R₇, —SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇,—SC(S)OR₇, —OC(O)NR₁₀R₁₁, —OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇,—NR₇C(NR₈)OR₇, —NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁,—SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇,—S(O)_(p)NR₁₀R₁₁, —SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁,—OP(O)(OR₇)₂, or —SP(O)(OR₇)₂;

k is 1, 2, 3, or 4; and

r is zero or an integer from 1 to 3, wherein R₇, R₈, R₁₀, R₁₁, and p aredefined as above.

In another embodiment of the compound represented by the above formula,R₁, R₃ and R₂₅ are each independently —OH, —SH, —NHR₇, —OC(O)NR₁₀R₁₁,—SC(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —OS(O)_(p)R₇,—S(O)_(p)OR₇, —SS(O)_(p)R₇, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —OC(S)R₇,—SC(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁,—OC(NR₈)R₇, —SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —OP(O)(OR₇)₂ or—SP(O)(OR₇)₂.

In another embodiment of the compound represented by the above formula,R₁ and R₃ are each, independently, —OH, —SH, or —NHR₇. In this case, R₆can be an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, cyano, halo, nitro, anoptionally substituted cycloalkyl, haloalkyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteroaralkyl, —OR₇, —SR₇, —NR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇,—NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇,—SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁,—NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇, —SS(O)_(p)R₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —C(O)NR₁₀R₁₁,—C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,or —S(O)_(p)R₇.

In another embodiment of the above compound, R₁ is —SH or —OH; R₃ andR₂₅ are —OH; R₆ is a lower alkyl, C3-C6 cycloalkyl, lower alkoxy, alower alkyl sulfanyl, or —NR₁₀R₁₁; and R₉, for each occurrence, isindependently selected from the group consisting of —OH, —SH, halo, alower haloalkyl, cyano, a lower alkyl, a lower alkoxy, and a lower alkylsulfanyl.

In another embodiment, in compounds represented by formula (I), or anyof the embodiments of formula (I) in which particular groups aredisclosed, R₁ and R₃ are each, independently, —OH, —SH, or —NHR₇.

In another embodiment, in compounds represented by formula (I), or anyof the embodiments of formula (I) in which particular groups aredisclosed, the compound is represented by the following structuralformula:

wherein R₁, R₃, R₅, and R₂₅ are defined as above; and

R₆ is an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, cyano, halo, nitro, anoptionally substituted cycloalkyl, haloalkyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteroaralkyl, —OR₇, —SR₇, —NR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇,—NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇,—SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁,—NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇, —SS(O)_(p)R₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —C(O)NR₁₀R₁₁,—C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,or —S(O)_(p)R₇, wherein R₇, R₈, R₁₀, R₁₁, and p are defined as above. Ina preferred embodiment, R₁ is —SH or —OH; R₃ and R₂₅ are —OH; R₁₂ is alower alkyl, lower alkoxy, a lower alkyl sulfanyl, or —NR₁₀R₁₁; and R₉,for each occurrence, is independently selected from the group consistingof —OH, —SH, halo, a lower haloalkyl, cyano, a lower alkyl, a loweralkoxy, and a lower alkyl sulfanyl.

In another embodiment, in compounds represented by formula (I), or anyof the embodiments of formula (I) in which particular groups aredisclosed, the compound is represented by one of the followingstructural formulas:

wherein R₁, R₃, R₅, R₆ and n are as defined above; and

X₃ and X₄ are each, independently, N, N(O), N⁺(R₁₇), CH or CR₆; and

X₅ is O, S, NR₁₇, CH═CH, CH═CR₆, CR₆═CH, CR₆═CR₆, CH═N, CR₆═N, CH═N(O),CR₆═N(O), N═CH, N═CR₆, N(O)═CH, N(O)═CR₆, N⁺(R₁₇)═CH, N⁺(R₁₇)═CR₆,CH═N⁺(R₁₇), CR₆═N⁺(R₁₇), or N═N; wherein R₁₇ is defined as above.

In another embodiment, in compounds represented by formula (I), or anyof the embodiments of formula (I) in which particular groups aredisclosed, the compound is selected from the group consisting of:

wherein R₁, R₃, R₅, and R₂₅ are defined as above.

In another aspect, the invention provides compounds of formula (II) asset forth below:

and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs thereof, wherein ring A, R₁ and R₃ are defined as above;and

R₂ is a substituted phenyl, wherein the phenyl group is substitutedwith:

-   -   i) one substituent selected from nitro, cyano, a haloalkoxy, an        optionally substituted alkenyl, an optionally substituted        alkynyl, an optionally substituted cycloalkyl, an optionally        substituted cycloalkenyl, an optionally substituted        heterocyclyl, an optionally substituted aryl, an optionally        substituted heteroaryl, an optionally substituted aralkyl, an        optionally substituted heteraralkyl, hydroxylalkyl, alkoxyalkyl,        guanadino, —NR₁₀R₁₁, —O—R₂₀, —C(O)R₇, —C(O)OR₂₀, —OC(O)R₇,        —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇,        —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁, or    -   ii) two to five substituents selected from the group consisting        of an optionally substituted alkyl, an optionally substituted        alkenyl, an optionally substituted alkynyl, an optionally        substituted cycloalkyl, an optionally substituted cycloalkenyl,        an optionally substituted heterocyclyl, an optionally        substituted aryl, an optionally substituted heteroaryl, an        optionally substituted aralkyl, an optionally substituted        heteraralkyl, hydroxyalkyl, alkoxyalkyl, —F, —Br, —I, cyano,        nitro, guanadino, a haloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇,        —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇,        —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or        —S(O)_(p)NR₁₀R₁₁;

R₂₀, for each occurrence, is independently an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl;

p, for each occurrence, is, independently, 1 or 2.

Compounds of formula (II) inhibit the activity of Hsp90 and areparticularly useful for treating or preventing (e.g., reducing thelikelihood of developing) angiogenesis related disorders, such asmacular degeneration. In addition, compounds of formula (II) areparticularly useful in reducing, blocking, occluding, or otherwisedisrupting blood flow in neovasculature.

In one embodiment, the compounds represented by formula (II) do notinclude3-(2,4-dihydroxy-phenyl)-4-(7-naphthalen-1-yl)-5-mercapto-triazole,3-(2,4-dihydroxyphenyl)-4-(2,5-dimethoxyphenyl)-5-mercapto-triazole,3-(1-phenyl-5-amino-pyrazol-4-yl)-4-(2,4-dichloropheny)-5-mercapto-triazole,and 3-(2-hydroxy-phenyl)4-(2,4-dimethylphenyl)-5-mercapto-triazole.

In another embodiment, in compounds represented by formula (II), or anyof the embodiments of formula (II) in which particular groups aredisclosed, the compound is represented by the following structuralformula:

wherein R₁, R₂, R₃, R₆, and n are defined as above.

In another embodiment, in compounds represented by formula (II), or anyof the embodiments of formula (II) in which particular groups aredisclosed, the compound is represented by the following structuralformula:

wherein R₁, R₂, R₃, R₆, R₂₅ and r are defined as above.

In another embodiment, in compounds represented by formula (II), or anyof the embodiments of formula (II) in which particular groups aredisclosed, R₁ and R₃ are each, independently, —OH, —SH, or —NHR₇.

In another embodiment, in compounds represented by formula (II), or anyof the embodiments of formula (II) in which particular groups aredisclosed, the compound is represented by the following structuralformula:

wherein R₁, R₂, R₃, R₆ and R₂₅ are defined as above. In a preferredembodiment, R₁ is —SH or —OH; R₃ and R₂₅ are —OH; R₁₂ is a lower alkyl,lower alkoxy, a lower alkyl sulfanyl, or —NR₁₀R₁₁; and R₉, for eachoccurrence, is independently selected from the group consisting of —OH,—SH, halo, a lower haloalkyl, cyano, a lower alkyl, a lower alkoxy, anda lower alkyl sulfanyl.

In another embodiment, in compounds represented by formula (II), or anyof the embodiments of formula (II) in which particular groups aredisclosed, the compound is represented by one of the followingstructural formulas:

wherein R₁, R₂, R₃, R₆, X₃, X₄, X₅ and n are defined as above.

In another embodiment, in compounds represented by formula (II), or anyof the embodiments of formula (II) in which particular groups aredisclosed, the compound is selected from the group consisting of:

wherein R₁, R₂, R₃, and R₂₅ are defined as above.

In another aspect, the invention provides compounds of formula (III) asset forth below:

and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs. In formula (III), ring A, R₁, and R₃ are defined as above;and

R₁₈ is an optionally substituted cycloalkyl, and optionally substitutedcycloalkenyl, or a substituted alkyl, wherein the alkyl group issubstituted with one or more substituents independently selected fromthe group consisting of an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, halo, cyano, nitro, guanadino, ahaloalkyl, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁, wherein R₇, R₈, R₁₀, R₁₁, and p aredefined as above.

Compounds of formula (III) inhibit the activity of Hsp90 and areparticularly useful for treating or preventing (e.g., reducing thelikelihood of developing) angiogenesis related disorders, such asmacular degeneration. In addition, compounds of formula (III) areparticularly useful in reducing, blocking, occluding, or otherwisedisrupting blood flow in neovasculature. In one embodiment, in formula(III) R₁₈ is not cyclohexyl.

In another embodiment, in formula (III) R₁₈ is an optionally substitutedcycloalkyl or an optionally substituted cycloalkenyl.

In another embodiment, in formula (III) R₁₈ is a substituted alkyl.

In another embodiment, in compounds represented by formula (III), or anyof the embodiments of formula (III) in which particular groups aredisclosed, the compound is represented by the following structuralformula:

wherein R₁, R₃, R₆, R₁₈, and n are defined as above.

In another embodiment, in compounds represented by formula (III), or anyof the embodiments of formula (III) in which particular groups aredisclosed, the compound is represented by the following structuralformula:

wherein R₁, R₃, R₆, R₁₈, R₂₅ and r are defined as above.

In another embodiment, in compounds represented by formula (III), or anyof the embodiments of formula (III) in which particular groups aredisclosed, R₁ and R₃ are each, independently, —OH, —SH, or —NHR₇.

In another embodiment, in compounds represented by formula (III), or anyof the embodiments of formula (III) in which particular groups aredisclosed, the compound is represented by the following structuralformula:

wherein R₁, R₃, R₆, R₁₈, and R₂₅ are defined as above. In a preferredembodiment, R₁ is —SH or —OH; R₃ and R₂₅ are —OH; and R₁₂ is a loweralkyl, lower alkoxy, a lower alkyl sulfanyl, or —NR₁₀R₁₁.

In another embodiment, in compounds represented by formula (III), or anyof the embodiments of formula (III) in which particular groups aredisclosed, the compound is represented by one of the followingstructural formulas:

wherein R₁, R₃, R₆, R₁₈, X₃, X₄, X₅, and n are defined as above.

In another embodiment, in compounds represented by formula (III), or anyof the embodiments of formula (III) in which particular groups aredisclosed, the compound is selected from the group consisting of:

wherein R₁, R₃, R₁₈, and R₂₅ are defined as above.

In another aspect, the invention provides compounds of formula (IV) or(V) as set forth below:

and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs thereof. In formulas (IV) and (V), R₁ and R₃ are as definedabove; and

X₁₄ is O, S, or NR₇;

R₂₁ is an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, or anoptionally substituted heteraralkyl;

R₂₂, for each occurrence, is independently an —H or is selected from thegroup consisting of an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl, a haloalkyl, —C(O)R₇, —C(O)OR₇,—OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —S(O)_(p)R₇, —S(O)_(p)OR₇, or—S(O)_(p)NR₁₀R₁₁; and

R₂₃ and R₂₄, for each occurrence, are independently —H or are selectedfrom the group consisting of an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, or an optionally substituted heteraralkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇,—C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇,—S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or—S(O)_(p)NR₁₀R₁₁;

wherein R₇, R₈, R₁₀, R₁₁ and p are defined as above.

In one embodiment, in formulas (IV) and (V), R₂₁ is an optionallysubstituted alkyl, an optionally substituted cycloalkyl, an optionallysubstituted aryl or an optionally substituted heteroaryl.

In another embodiment, in the formulas (IV) and (V), R₁ is —OH, —SH, or—NHR₇.

In another embodiment, in the formulas (IV) and (V), R₂₂ is —H, analkyl, an aralkyl, —C(O)R₇, or —C(O)NR₁₀R₁₁.

In another embodiment, in the formulas (IV) and (V), X₁₄ is O.

Compounds of formula (IV) or (V) inhibit the activity of Hsp90 and areparticularly useful for treating or preventing (e.g., reducing thelikelihood of developing) angiogenesis related disorders, such asmacular degeneration. In addition, compounds of formula (IV) or (V) areparticularly useful in reducing, blocking, occluding, or otherwisedisrupting blood flow in neovasculature.

In another aspect, the invention provides compounds represented byformula (VI):

and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs thereof, wherein:

X₄₁ is O, S, or NR₄₂;

X₄₂ is CR₄₄ or N;

Y₄₀ is N or CR₄₃;

Y₄₁ is N or CR₄₅;

Y₄₂, for each occurrence, is independently N, C or CR₄₆;

Z is OH, SH, or NHR₇;

R₄₁ is —H, —OH, —SH, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, halo, cyano, nitro, guanadino, ahaloalkyl, a heteroalkyl, an alkoxy or cycloalkoxy, a haloalkoxy,—NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇, —C(S)SR₇,—C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂;

R₄₂ is —H, an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, a haloalkyl, aheteroalkyl, —C(O)R₇, —(CH₂)_(m)C(O)OR₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —S(O)_(p)R₇, —S(O)_(p)OR₇, or —S(O)_(p)NR₁₀R₁₁;

R₄₃ and R₄₄ are, independently, —H, —OH, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl,hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, aheteroalkyl, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇,—S(O)_(p)NR₁₀R₁₁, or R₄₃ and R₄₄ taken together with the carbon atoms towhich they are attached form an optionally substituted cycloalkenyl, anoptionally substituted aryl, an optionally substituted heterocyclyl, oran optionally substituted heteroaryl;

R₄₅ is —H, —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH,—O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH,—S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇,—OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇,—NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁,—OS(O)_(p)R₇, —SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁,—SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇,—NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇,—NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇,—OC(NR₈)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁, or —NR₇C(NR₈)NR₁₀R₁₁;

R₄₆, for each occurrence, is independently selected from the groupconsisting of H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, halo, cyano, nitro, guanadino, ahaloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇,—C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁;

R₇, R₈, R₁₀, R₁₁, R₂₆, p, and m are defined as above.

In one embodiment, in formula (VI), X₄₁ is NR₄₂ and X₄₂ is CR₄₄.

In another embodiment, in formula (VI), X₄₁ is NR₄₂ and X₄₂ is N.

In another embodiment, in formula (VI), R₄₁ is selected from the groupconsisting of —H, lower alkyl, lower alkoxy, lower cycloalkyl, and lowercycloalkoxy.

In another embodiment, in formula (VI), R₄₁ is selected from the groupconsisting of —H, methyl, ethyl, propyl, isopropyl, cyclopropyl,methoxy, ethoxy, propoxy, and cyclopropoxy.

In another embodiment, in formula (VI), X₄₁ is NR₄₂, and R₄₂ is selectedfrom the group consisting of —H, a lower alkyl, a lower cycloalkyl,—C(O)N(R₂₇)₂, and —C(O)OH, wherein R₂₇ is —H or a lower alkyl.

In another embodiment, in formula (VI), X₄₁ is NR₄₂, and R₄₂ is selectedfrom the group consisting of —H, methyl, ethyl, n-propyl, isopropyl,cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, —C(O)OH,—(CH₂)_(m)C(O)OH, —CH₂OCH₃, —CH₂CH₂OCH₃, and —C(O)N(CH₃)₂.

In one embodiment, Y₄₀ is CR₄₃. Preferably, Y₄₀ is CR₄₃ and R₄₃ is H ora lower alkyl.

In another embodiment, in formula (VI), R₄₃ and R₄₄ are, independently,selected from the group consisting of —H, methyl, ethyl, propyl,isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy.

In another embodiment, in formula (VI), X₄₂ is CR₄₄; Y is CR₄₃; and R₄₃and R₄₄ together with the carbon atoms to which they are attached form acycloalkenyl, an aryl, heterocyclyl, or heteroaryl ring. In one aspectof this embodiment, R₄₃ and R₄₄ together with the carbon atoms to whichthey are attached form a C₅-C₈ cycloalkenyl or a C₅-C₈ aryl.

In another embodiment, in formula (VI), R₄₅ is selected from the groupconsisting of —H, —OH, —SH, —NH₂, a lower alkoxy, a lower alkyl amino,and a lower dialkyl amino.

In another embodiment, in formula (VI), R₄₅ is selected from the groupconsisting of —H, —OH, methoxy and ethoxy.

In another embodiment, in formula (VI), X₄₁ is O.

In another embodiment, the compound is selected from the groupconsisting of:

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2-methyl-7-methoxy-benzofuran-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(benzofuran-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2-methyl-1,3-benzoxaz-5-yl)-5-mercapto-[1,2,4]triazole,and

tautomers, pharmaceutically acceptable salts, solvates, clathrates, andprodrugs thereof.

In another embodiment, in formula (VI), Z is —OH.

In another embodiment, the compound is selected from the groupconsisting of:

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,

3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,

3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,

3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-isopropyl-indol-4-yl)-5-hydroxy-[1,2,4]triazole,and

tautomers, pharmaceutically acceptable salts, solvates, clathrates, andprodrugs thereof.

In another embodiment, Z is —SH.

In another embodiment, the compound is selected from the groupconsisting of:

3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indazol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indazol-6-yl)-5-mercapto-[1,2,4]triazole,and

tautomers, pharmaceutically acceptable salts, solvates, clathrates, andprodrugs thereof.

Compounds of formula (VI) inhibit the activity of Hsp90 and areparticularly useful for treating or preventing (e.g., reducing thelikelihood of developing) angiogenesis related disorders, such asmacular degeneration. In addition, compounds of formula (VI) areparticularly useful in reducing, blocking, occluding, or otherwisedisrupting blood flow in neovasculature.

In another aspect, the invention provides compounds represented byformula (VII):

and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs thereof, wherein:

Z₁ is —OH or —SH;

X₄₂, R₄₁, R₄₂, R₄₃, and R₄₅ are defined as above.

In one embodiment, in formula (VII), Z₁ is —OH.

In another embodiment, in formula (VII), Z₁ is —SH.

In another embodiment, in formula (VII), R₄₁ is selected from the groupconsisting of —H, lower alkyl, lower alkoxy, lower cycloalkyl, and lowercycloalkoxy.

In another embodiment, in formula (VII), R₄₁ is selected from the groupconsisting of —H, methyl, ethyl, propyl, isopropyl, cyclopropyl,methoxy, ethoxy, propoxy, and cyclopropoxy.

In another embodiment, in formula (VII), R₄₂ is selected from the groupconsisting of lower alkyl, lower cycloalkyl, —C(O)N(R₂₇)₂, or —C(O)OH,wherein R₂₇ is —H or a lower alkyl.

In another embodiment, in formula (VII), R₄₂ is selected from the groupconsisting of —H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl,n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, —C(O)OH,—(CH₂)_(m)C(O)OH, —CH₂OCH₃, —CH₂CH₂OCH₃, and —C(O)N(CH₃)₂.

In another embodiment, R₄₃ is H or a lower alkyl.

In another embodiment, in formula (VII), X₄₂ is CR₄₄, and R₄₃ and R₄₄are, independently, selected from the group consisting of —H, methyl,ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, andcyclopropoxy.

In another embodiment, in formula (VII), X₄₂ is CR₄₄, and R₄₃ and R₄₄,taken together with the carbon atoms to which they are attached, form acycloalkenyl, aryl, heterocyclyl, or heteroaryl ring. Preferably, inthis embodiment, R₄₃ and R₄₄, taken together with the carbon atoms towhich they are attached, form a C₅-C₈ cycloalkenyl or a C₅-C₈ aryl.

In another embodiment, in formula (VII), R₄₅ is selected from the groupconsisting of —H, —OH, —SH, —NH₂, a lower alkoxy, a lower alkyl amino,and a lower dialkyl amino.

In another embodiment, in formula (VII), R₄₅ is selected from the groupconsisting of —H, —OH, methoxy, and ethoxy.

In another embodiment, in formula (VII), X₄₃ is CR₄₄.

In another embodiment, the compound is selected from the groupconsisting of:

3-(2,4-dihydroxyphenyl)-4-(1-ethyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxyphenyl)-4-(1-isopropyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxyphenyl)-4-(indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxyphenyl)-4-(1-methoxyethyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxyphenyl)-4-(1-dimethylcarbamoyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-propyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,2,3-trimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-acetyl-2,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-propyl-2,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-methyl-tetrahydrocarbozol-7-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-methyl-cyclononan[a]indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-n-butyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-n-pentyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-n-hexyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1-(1-methylcyclopropyl)-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1,2,3-trimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazoledisodium salt,

3-(2,4-dihydroxy-5-tert-butyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1-propyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-methyl-3-ethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-methyl-3-isopropyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-ethyl-carbozol-7-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-7-hydroxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-7-ethoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,2-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-methyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1H-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,2-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-ethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-propyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,and

tautomers, pharmaceutically acceptable salts, solvates, clathrates, andprodrugs thereof.

In another embodiment, in formula (VII), X₄₂ is N.

In another embodiment, the compound is selected from the groupconsisting of

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-ethyl-benzimidazol-4-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-ethyl-benzimidazol-4-yl)-5-mercapto-[1,2,4]triazole HCL salt,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2-methyl-3-ethyl-benzimidazol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-ethyl-2-methyl-benzimidazol-5-yl)-5-mercapto-[1,2,4]triazole,

3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-2-trifluoromethyl-benzimidazol-5-yl)-5-mercapto-[1,2,4]triazole,and

tautomers, pharmaceutically acceptable salts, solvates, clathrates, andprodrugs thereof.

Compounds of formula (VII) inhibit the activity of Hsp90 and areparticularly useful for treating or preventing (e.g., reducing thelikelihood of developing) angiogenesis related disorders, such asmacular degeneration. In addition, compounds of formula (VII) areparticularly useful in reducing, blocking, occluding, or otherwisedisrupting blood flow in neovasculature.

In another aspect, the invention provides compounds represented byformula (VIII):

and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs thereof, wherein:

X₄₅ is CR₅₄ or N;

Z₁ is —OH or —SH;

R₅₂ is selected from the group consisting of —H, methyl, ethyl,n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, —(CH₂)₂OCH₃,—CH₂C(O)OH, and —C(O)N(CH₃)₂;

R₅₃ and R₅₄ are each, independently, —H, methyl, ethyl, or isopropyl; orR₅₃ and R₅₄ taken together with the carbon atoms to which they areattached form a phenyl, cyclohexenyl, or cyclooctenyl ring;

R₅₅ is selected from the group consisting of —H, —OH, —OCH₃, and—OCH₂CH₃; and

R₅₆ is selected from the group consisting of —H, methyl, ethyl,isopropyl, and cyclopropyl.

In one embodiment, in formula (VIII), Z₁ is —OH.

In another embodiment, in formula (VIII), Z₁ is —SH.

In another embodiment, in formula (VIII), R₅₃ is H or a lower alkyl.

In another embodiment, in formula (VIII), X₄₅ is CR₅₄. Preferably, R₅₄is H or a lower alkyl.

In another embodiment, X₄₅ is N.

In another embodiment, the compound is3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(N-methyl-indol-5-yl)-5-mercapto-[1,2,4]triazole.

Compounds of formula (VIII) inhibit the activity of Hsp90 and areparticularly useful for treating or preventing (e.g., reducing thelikelihood of developing) angiogenesis related disorders, such asmacular degeneration. In addition, compounds of formula (VIII) areparticularly useful in reducing, blocking, occluding, or otherwisedisrupting blood flow in neovasculature.

In another aspect, the invention provides compounds represented byformula (IX):

and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs thereof, wherein,

X₄₄, for each occurrence, is independently, O, NR₄₂ or C(R₄₆)₂;

Y₄₃ is NR₄₂ or C(R₄₆)₂;

Y₄₁, Y₄₂, Z, R₄₁, R₄₂, and R₄₆ are defined as above.

In one embodiment, in formula (IX), R₄₁ is selected from the groupconsisting of —H, lower alkyl, lower alkoxy, lower cycloalkyl, and lowercycloalkoxy.

In another embodiment, in formula (IX), R₄₁ is selected from the groupconsisting of —H, methyl, ethyl, propyl, isopropyl, cyclopropyl,methoxy, ethoxy, propoxy, and cyclopropoxy.

In another embodiment, in formula (IX), R₄₂ is selected from the groupconsisting of —H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl,n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, —C(O)OH,—(CH₂)_(m)C(O)OH, —CH₂OCH₃, —CH₂CH₂OCH₃, and —C(O)N(CH₃)₂.

In another embodiment, in formula (IX), Y₄₁ is CR₄₅. Preferably, R₄₅ isH, a lower alkoxy, or —OH.

In another embodiment, in formula (IX), Y₄₂ is CH.

In another embodiment, in formula (IX), Y₄₃ is CH₂.

In another embodiment, in formula (IX), Y₄₃ is NR₄₂, wherein R₄₂ is H ora lower alkyl.

In another embodiment, in formula (IX), one of X₄₄ is NR₄₂ and the otheris CH₂ or C(R₆)₂. Preferably, one of X₄₄ is NR₄₂ and the other is CH₂.

In another embodiment, in formula (VI), Z is —OH.

In another embodiment, Z is —SH.

Compounds of formula (IX) inhibit the activity of Hsp90 and areparticularly useful for treating or preventing (e.g., reducing thelikelihood of developing) angiogenesis related disorders, such asmacular degeneration. In addition, compounds of formula (IX) areparticularly useful in reducing, blocking, occluding, or otherwisedisrupting blood flow in neovasculature.

In another aspect, the invention provides compounds represented byformula (X):

and tautomers, pharmaceutically acceptable salts, solvates, clathrates,and prodrugs thereof, wherein:

X₄₁, Y₄₁, Y₄₂, Z, R₇, R₈, R₁₀, R₁₁, R₄₁, R₄₆, and p are defined asabove.

In one embodiment, in formula (X), R₄₁ is selected from the groupconsisting of —H, lower alkyl, lower alkoxy, lower cycloalkyl, and lowercycloalkoxy.

In another embodiment, in formula (X), R₄₁ is selected from the groupconsisting of —H, methyl, ethyl, propyl, isopropyl, cyclopropyl,methoxy, ethoxy, propoxy, and cyclopropoxy.

In another embodiment, in formula (X), X₄₁ is NR₄₂. Preferably, R₄₂ isselected from the group consisting of —H, methyl, ethyl, n-propyl,isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl,n-hexyl, —C(O)OH, —(CH₂)_(m)C(O)OH, —CH₂OCH₃, —CH₂CH₂OCH₃, and—C(O)N(CH₃)₂. More preferably, R₄₂ is H or a lower alkyl.

In another embodiment, in formula (X), X₄₁ is O.

In another embodiment, in formula (X), X₄₁ is S.

In another embodiment, in formula (X), Y₄₁ is CR₄₅. Preferably, R₄₅ isH, a lower alkoxy, or —OH.

In another embodiment, in formula (X), Y₄₂ is CH.

In another embodiment, in formula (X), R₄₆ is H or a lower alkyl.

In one embodiment, the compound is3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(2-methyl-indazol-6-yl)-5-mercapto-[1,2,4]triazole.

Compounds of formula (X) inhibit the activity of Hsp90 and areparticularly useful for treating or preventing (e.g., reducing thelikelihood of developing) angiogenesis related disorders, such asmacular degeneration. In addition, compounds of formula (X) areparticularly useful in reducing, blocking, occluding, or otherwisedisrupting blood flow in neovasculature.

i) Exemplary Compounds of the Invention

Exemplary compounds of the invention are depicted in Table 1 below,including tautomers, pharmaceutically acceptable salts, solvates,clathrates, hydrates, polymorphs or prodrugs thereof.

TABLE 1 No. Structure Tautomeric Structure Name 1

3-(2- Hydroxyphenyl)- 4-(naphthalen-1- yl)-5-mercapto- [1,2,4] triazole2

3-(2,4- Dihydroxyphenyl)- 4-[4-(2- methoxyethoxy)- naphthalen-1-yl]-5-mercapto- [1,2,4] triazole 3

3-(2,4- Dihydroxyphenyl)- 4-(2-methyl-4- bromophenyl)-5-mercapto-[1,2,4] triazole 4

3-(2,4- Dihydroxyphenyl)- 4-(4- bromophenyl)-5- mercapto-[1,2,4]triazole 5

3-(3,4- Dihydroxyphenyl)- 4-(6-methoxy- naphthalen-1-yl)- 5-mercapto-[1,2,4] triazole 6

3-(3,4- Dihydroxyphenyl)- 4-(6-ethoxy- naphthalen-1-yl)- 5-mercapto-[1,2,4] triazole 7

3-(3,4- Dihydroxyphenyl)- 4-(6-propoxy- naphthalen-1-yl)- 5-mercapto-[1,2,4] triazole 8

3-(2,4-Dihydroxy- 5-ethyl-phenyl)-4- (5-methoxy- naphthalen-1-yl)-5-mercapto- [1,2,4] triazole 9

3-(3,4- Dihydroxyphenyl)- 4-(6-isopropoxy- naphthalen-1-yl)- 5-mercapto-[1,2,4] triazole 10

3-(2,4- Dihydroxyphenyl)- 4-(2,6- diethylphenyl)-5- mercapto-[1,2,4]triazole 11

3-(2,4- Dihydroxyphenyl)- 4-(2-methyl-6- ethylphenyl)-5-mercapto-[1,2,4] triazole 12

3-(2,4- Dihydroxyphenyl)- 4-(2,6- diisopropylphenyl)- 5-mercapto-[1,2,4] triazole 13

3-(2,4- Dihydroxyphenyl)- 4-(1-ethyl-indol- 4-yl)-5-mercapto- [1,2,4]triazole 14

3-(2,4- Dihydroxyphenyl)- 4-(2,3-dihydro- benzo[1,4]dioxin-5-yl)-5-mercapto- [1,2,4] triazole 15

3-(2,4- Dihydroxyphenyl)- 4-(3- methylphenyl)-5- mercapto-[1,2,4]triazole 16

3-(2,4- Dihydroxyphenyl)- 4-(4- methylphenyl)-5- mercapto-[1,2,4]triazole 17

3-(2,4- Dihydroxyphenyl)- 4-(2- chlorophenyl)-5- mercapto-[1,2,4]triazole 18

3-(2,4- Dihydroxyphenyl)- 4-(3- chlorophenyl)-5- mercapto-[1,2,4]triazole 19

3-(2,4- Dihydroxyphenyl)- 4-(4- chlorophenyl)-5- mercapto-[1,2,4]triazole 20

3-(2,4- Dihydroxyphenyl)- 4-(2- methoxyphenyl)- 5-mercapto- [1,2,4]triazole 21

3-(2,4- Dihydroxyphenyl)- 4-(3- methoxyphenyl)- 5-mercapto- [1,2,4]triazole 22

3-(2,4- Dihydroxyphenyl)- 4-(4- methoxyphenyl)- 5-mercapto- [1,2,4]triazole 23

3-(2,4- Dihydroxyphenyl)- 4-(3- fluorophenyl)- 5-mercapto- [1,2,4]triazole 24

3-(2,4- Dihydroxyphenyl)- 4-(2- ethylphenyl)- 5-mercapto- [1,2,4]triazole 25

3-(2-Hydroxy-4- fluorophenyl)-4- (naphthalen-1-yl)- 5-mercapto- [1,2,4]triazole 26

3-(2-Hydroxy-4- aminophenyl)-4- (naphthalen-1-yl)- 5-mercapto- [1,2,4]triazole 27

3-(2,4- Dihydroxyphenyl)- 4-(2-methyl-4- butyl-phenyl)-5-mercapto-[1,2,4] triazole 28

3-(2,4- Dihydroxyphenyl)- 4-(2,4-dimethyl- phenyl)-5- mercapto-[1,2,4]triazole 29

3-(2,4- Dihydroxyphenyl)- 4-(2,6-dimethyl- phenyl)-5- mercapto-[1,2,4]triazole 30

3-(2,4- Dihydroxyphenyl)- 4-(2,6-dimethyl- phenyl)-5- mercapto-[1,2,4]triazole 31

3-(2,4- Dihydroxyphenyl)- 4-(4- fluorophenyl)-5- mercapto-[1,2,4]triazole 32

3-(2,4- Dihydroxyphenyl)- 4-(2- methylsulfanyl- phenyl)-5-mercapto-[1,2,4] triazole 33

3-(2,4- Dihydroxyphenyl)- 4-(naphthalene- 2-yl)-5-mercapto- [1,2,4]triazole 34

3-(2,4- Dihydroxyphenyl)- 4-(2,3- dimethylphenyl)- 5-mercapto- [1,2,4]triazole 35

3-(2,4- Dihydroxyphenyl)- 4-(2-methyl-4- fluorophenyl)-5-mercapto-[1,2,4] triazole 36

3-(2,4- Dihydroxyphenyl)- 4- (acenaphthalen- 5-yl)-5-mercapto- [1,2,4]triazole 37

3-(2-Hydroxy-4- methoxy-phenyl)-4- (naphthalen-1-yl)- 5-mercapto-[1,2,4] triazole 38

3-(2,4- Dihydroxyphenyl)- 4-(2,3- dichlorophenyl)-5- mercapto-[1,2,4]triazole 39

3-(2,4- Dihydroxyphenyl)- 4-(5- methoxynaphthalen- 1-yl)-5-mercapto-[1,2,4] triazole 40

3-(2,4- Dihydroxyphenyl)- 4-(pyren-1-yl)-5- mercapto-[1,2,4] triazole 41

3-(2,4- Dihydroxyphenyl)- 4-(quinolin-5-yl)-5- mercapto-[1,2,4] triazole42

3-(2,4- Dihydroxyphenyl)- 4-(1,2,3,4- tetrahydronaphthalen- 5-yl)-5-mercapto-[1,2,4] triazole 43

3-(2,4- Dihydroxyphenyl)- 4- (anthracen-1- yl)-5-mercapto- [1,2,4]triazole 44

3-(2,4- Dihydroxyphenyl)- 4-(biphenyl-2-yl)- 5-mercapto- [1,2,4]triazole 45

3-(2,4-Dihydroxy- 6-methyl-phenyl)- 4-(naphthalene-1- yl)-5-mercapto-[1,2,4] triazole 46

3-(2,4- Dihydroxyphenyl)- 4-(4- pentyloxyphenyl)- 5-mercapto- [1,2,4]triazole 47

3-(2,4- Dihydroxyphenyl)- 4-(4- octyloxyphenyl)- 5-mercapto- [1,2,4]triazole 48

3-(2,4- Dihydroxyphenyl)- 4-(4- chloronaphthalen- 1-yl)-5-mercapto-[1,2,4] triazole 49

3-(2,4-Dihydroxy- 5-ethyl-phenyl)-4- (naphthalen-1-yl)- 5-mercapto-[1,2,4] triazole 50

3-(2,4-Dihydroxy- 5-ethyl-phenyl)-4- (7- carboxymethoxy-naphthalen-1-yl)- 5-mercapto- [1,2,4] triazole 51

3-(2,4- Dihydroxyphenyl)- 4-(2-methyl- quinolin-4-yl)-5- mercapto-[1,2,4] triazole 52

3-(3- Hydroxypyridin-4- yl)-4-(naphthalen- 1-yl)-5-mercapto- [1,2,4]triazole 53

3-(2-Hydroxy-4- acetylamino- phenyl)-4- (naphthalen-1-yl)- 5-mercapto-[1,2,4] triazole 54

3-(2,4-Dihydroxy- phenyl)- 4-(1,2,3,4- tetrahydronaphthalen- 1-yl)-5-mercapto- [1,2,4] triazole 55

3-(2,4-Dihydroxy- phenyl)- 4-(2,3- dihydro- benzo[1,4]dioxin-5-yl)-5-mercapto- [1,2,4] triazole 56

3-(2,4-Dihydroxy- phenyl)- 4-(3,5- dimethoxyphenyl)- 5-mercapto- [1,2,4]triazole 57

3-(2,4-Dihydroxy- phenyl)- 4-(2,3- dimethyl-1H- indol-4-yl)-5-mercapto-[1,2,4] triazole 58

3-(2,4-Dihydroxy- 3-propyl-phenyl)- 4-(naphthalen-1- yl)-5-mercapto-[1,2,4] triazole 59

3-(1-ethyl-5- hydroxy-6-oxo- 1,6-dihydro- pyridin-3-yl)-4-(naphthalen-1-yl)- 5-mercapto- [1,2,4] triazole 60

3-(4-hydroxy-6- oxopyridin-3-yl)- 4-(naphthalen-1- yl)-5-mercapto-[1,2,4] triazole 61

3-(2,4-Dihydroxy- phenyl)-4-(3,5-di- tert-butylphenyl)- 5-mercapto-[1,2,4] triazole 62

3-(2,6- Dihydroxy5- fluoro-pyridin-3- yl) 4-(naphthalen-1-yl)-5-mercapto- [1,2,4] triazole 63

3-(2,4-Dihydroxy- 5-methyl-phenyl)- 4-(naphthalene-1- yl)-5-mercapto-[1,2,4] triazole 64

3-[2,4-Dihydroxy- phenyl]-4-(3- benzophenyl)-5- mercapto- [1,2,4]triazole 65

3-(2,4-Dihydroxy- phenyl)-4-(4- carboxy- naphthalen-1-yl)- 5-mercapto-[1,2,4] triazole 66

3-(2,4-Dihydroxy- phenyl)-4-[4- (N,N- dimethylcarbamoyl)- naphthalen-1-yl]-5-mercapto- [1,2,4] triazole 67

3-(2,4-Dihydroxy- phenyl)-4-(4- propoxy- naphthalen-1-yl)- 5-mercapto-[1,2,4] triazole 68

3-(2,4-Dihydroxy- phenyl)-4-(4- isopropoxy- naphthalen-1-yl)-5-mercapto- [1,2,4] triazole 69

3-(2,4-Dihydroxy- phenyl)-4-(5- isopropoxy- naphthalen-1-yl)-5-mercapto- [1,2,4] triazole 70

3-(2,4-Dihydroxy- phenyl)-4- (isoquinolin-5-yl)- 5-mercapto- [1,2,4]triazole 71

3-(2,4-Dihydroxy- phenyl)-4-(5- propoxy- naphthalen-1-yl)- 5-mercapto-[1,2,4] triazole 72

3-(2-Hydroxy-4- methanesulfonamino- phenyl)-4- (naphthalen-1-yl)-5-mercapto- [1,2,4] triazole 73

3-(2,4-Dihydroxy- 3,6-dimethyl- phenyl)-4- (naphthalen-1-yl)-5-mercapto- [1,2,4] triazole 74

3-(2,4-Dihydroxy- phenyl)-4-[7-(2- methoxyethoxy)- naphthalen-1-yl]-5-mercapto- [1,2,4] triazole 75

3-(2,4-Dihydroxy- 5-hexyl-phenyl)- 4-(naphthalen-1-yl)- 5-mercapto-[1,2,4] triazole 76

3-(2,4-Dihydroxy- 5-ethyl-phenyl)-4- (4-methoxy- naphthalen-1-yl)-5-mercapto- [1,2,4] triazole 77

3-(2,4-Dihydroxy- 5-ethyl-phenyl)-4- (6-methoxy- naphthalin-1-yl)-5-mercapto- [1,2,4] triazole 78

3-(2,4-Dihydroxy- 3-chloro-5-ethyl- phenyl)-4- (naphthalen-1-yl)-5-mercapto- [1,2,4] triazole 79

3-(2,4-Dihydroxy- 5-ethyl-phenyl)-4- (2,3-dimethy-4- methoxy-phenyl)-5-mercapto- [1,2,4] triazole 80

3-(2,4-Dihydroxy- phenyl)-4-(7- isopropoxy- naphthalen-1-yl)-5-mercapto- [1,2,4] triazole 81

3-(2,4-Dihydroxy- phenyl)-4-(7- ethoxy- naphthalen-1-yl)- 5-mercapto-[1,2,4] triazole 82

3-(2,4-Dihydroxy- phenyl)-4-(7- propoxy- naphthalen-1-yl)- 5-mercapto-[1,2,4] triazole 83

3-(2-Hydroxy-4- methoxymethyoxy- phenyl)-4- (naphthalen-1-yl)-5-mercapto- [1,2,4] triazole 84

3-[2-Hydroxy-4- (2-hydroxy- ethoxy)-phenyl]- 4-(naphthalen-1-yl)-5-mercapto- [1,2,4] triazole 85

3-(2,4- Dihydroxyphenyl)- 4-(7-methoxy- naphthalen-1-yl)- 5-mercapto-[1,2,4] triazole 86

3-(2,4- Dihydroxyphenyl)- 4-(5-methoxy- naphthalen-1-yl)- 5-mercapto-[1,2,4] triazole 87

3-(2,4- Dihydroxyphenyl)- 4-(4-hydroxy- naphthalen-1-yl)- 5-mercapto-[1,2,4] triazole 88

3-(2,4- Dihydroxyphenyl)- 4-(1-isopropyl- indol-4-yl)-5-mercapto-[1,2,4] triazole 89

3-(2,4-Dihydroxy- 5-tert-butyl- phenyl)-4- (naphthalen-1-yl)-5-mercapto- [1,2,4] triazole 90

3-(2,4-Dihydroxy- 5-propyl-phenyl)- 4-(naphthalen-1-yl)- 5-mercapto-[1,2,4] triazole 91

3-(2,4-Dihydroxy- 3-methyl-5-ethyl- phenyl)-4- (naphthalen-1-yl)-5-mercapto- [1,2,4] triazole 92

3-(2,4-Dihydroxy- 5-isobutyl- phenyl)-4- (naphthalen-1-yl)- 5-mercapto-[1,2,4] triazole 93

3-(2,4-Dihydroxy- phenyl)-4-(2,3- dimethoxy- phenyl)-5- mercapto-[1,2,4]triazole 94

3-(2,4-Dihydroxy- phenyl)-4-(2- methoxy-3- chloro-phenyl)-5-mercapto-[1,2,4] triazole 95

3-(2,4-Dihydroxy- phenyl)-4-(indol- 4-yl)-5- mercapto- [1,2,4] triazole96

3-(2,4-Dihydroxy- phenyl)-4-[1-(2- methoxyethoxy)- indol-4-yl]-5-mercapto-[1,2,4] triazole 97

3-(2,4-Dihydroxy- phenyl)-4- (naphthalen-1-yl)- 5-hydroxy-[1,2,4]triazole 98

3-(1-Oxo-3- hydroxy-pyridin- 4-yl)-4- (naphthalen-1-yl)- 5-mercapto-[1,2,4] triazole 99

3-(2,5-Dihydroxy- 4-carboxy)-4- (naphthalen-1-yl)- 5-mercapto- [1,2,4]triazole 100

3-(2,4-Dihydroxy- 5-ethyl-phenyl)-4- (1-isopropyl- indol-4-yl)-5-mercapto-[1,2,4] triazole 101

3-(2,4-Dihydroxy- 5-ethyl-phenyl)-4- [1-(dimethyl- carbamoyl)-indol-4-yl]-5-mercapto- [1,2,4] triazole 102

3-(2,4-Dihydroxy- 5-ethyl-phenyl)-4- (1-ethyl- benzoimidazol-4-yl)-5-mercapto- [1,2,4] triazole 103

3-(2,4-Dihydroxy- 5-ethyl-phenyl)-4- (1,2,3-trimethyl- indol-5-yl)-5-mercapto-[1,2,4] triazole 104

3-(2,4-Dihydroxy- 4-hydroxymethyl- phenyl)-4- (naphthalen-1-yl)-5-mercapto- [1,2,4] triazole 105

3-(2-Hydroxy-4- amino-phenyl)-4- (naphthalen-1-yl)- 5-mercapto- [1,2,4]triazole 106

3-(2-Hydroxy-4- acetylamino- phenyl)-4- (naphthalen-1-yl)- 5-mercapto-[1,2,4] triazole 107

3-(2,4-Dihydroxy- 3-chloro-phenyl)- 4-(naphthalen-1-yl)- 5-mercapto-[1,2,4] triazole 108

3-(2,4-Dihydroxy- phenyl)-4- (naphthalen-1-yl)- 5-mercapto- [1,2,4]triazole 109

3-(2,4-Dihydroxy- phenyl)-4-(2- methyl-phenyl)-5- mercapto- [1,2,4]triazole 110

3-(2,4-Dihydroxy- phenyl)-4-(2,5- dimethoxy- phenyl)-5- mercapto-[1,2,4] triazole 111

3-(2,4-Dihydroxy- phenyl)-4-phenyl- 5-mercapto- [1,2,4] triazole 112

3-(2-Hydroxy- phenyl)-4-(2- methoxy-phenyl)- 5-mercapto- [1,2,4]triazole 113

3-(2-Hydroxy- phenyl)-4-(4- methyl-phenyl)- 5-mercapto- [1,2,4] triazole114

3-(2-Hydroxy- phenyl)-4-(4- bromo-phenyl)- 5-mercapto- [1,2,4] triazole115

3-(2,4-Dihydroxy- phenyl)-4- (naphthalen-1-yl)- 5-(methylsulfanyl)-[1,2,4] triazole 116

3-(2,4- Dimethoxy phenyl)-4- (naphthalen-1-yl)- 5-mercapto- [1,2,4]triazole 117

3-[2,4- (dimethyl- carbamoyloxy)- phenyl]-4- (naphthalen-1-yl)-5-(dimethyl- carbamoylsulfanyl)- [1,2,4] triazole 118

3-(2,4-Dihydroxy- phenyl)-4- (naphthalen-1-yl)- 5- (dimethylcarbamoyl-sulfanyl)- [1,2,4] triazole 119

3-(2,4- Diethoxycarbonyl oxy-phenyl)-4- (naphthalen-1-yl)- 5-(ethoxycarbonyl- sulfanyl)- [1,2,4] triazole 120

3-(2,4-Di- isobutyryloxyl- phenyl)-4- (naphthalen-1-yl)- 5-(isobutyrylsulfanyl)- [1,2,4] triazole 121

3-[2,4-Di- (dimethyl- carbamoyloxy)- phenyl]-4- (quinolin-5-yl)-5-(dimethyl- carbamoylsulfanyl)- [1,2,4] triazole 122

3-[2,4-Diacetoxy- phenyl)-4- (naphthalen-1-yl)- 5-(acetylsulfanyl)-[1,2,4] triazole 123

3-(2,4-Diacetoxy- phenyl)-4- (naphthalen-1-yl)- 5-mercapto- [1,2,4]triazole 124

3-(2,4- Diethylcarbamoyl oxy-phenyl)-4- (naphthalen-1-yl)- 5-(ethylcarbamoyl- sulfanyl)- [1,2,4] triazole 125

3-(2,4-Dihydroxy- phenyl)-4- (naphthalen-1-yl)- 5-(2- hydroxyethyl-sulfanyl)- [1,2,4] triazole 126

3-(2,4-Dihydroxy- phenyl)-4-ethyl-5- mercapto-[1,2,4] triazole 127

3-(2,4-Dihydroxy- phenyl)-4-propyl- 5-mercapto [1,2,4] triazole 128

3-(2,4-Dihydroxy- phenyl)-4- isopropyl-5- mercapto-[1,2,4] triazole 129

3-(2,4-Dihydroxy- phenyl)-4-butyl-5- mercapto-[1,2,4] triazole 130

3-(2,4-Dihydroxy- phenyl)-4- cyclopropyl-5- mercapto-[1,2,4] triazole131

3-(2,4-Dihydroxy- phenyl)-4- (naphthalen-1-yl)- 5- (carboxyethysulfanyl-[1,2,4] triazole 132

3-(2,6- Dimethoxy-5- fluoro-pyridin-3- yl)-4-(naphthalen-1-yl)-5-mercapto- [1,2,4] triazole 133

3-(2- Methanesulfonyloxy- 4- methanesulfonyl- amino- phenyl)-4-(naphthalen-1-yl)- 5-mercapto- [1,2,4] triazole 134

3-(2-Methoxy- phenyl)-4-(4- methoxy-phenyl)- 5-mercapto-[1,2,4] triazole135

3-(3-Hydroxy- naphthalen-2-yl)- 4-phenyl-5- mercapto-[1,2,4] triazole136

3-(2-Methoxy- phenyl)-4-(4- methyl-phenyl)-5- mercapto-[1,2,4] triazole137

3-(2,4-Dihydroxy- 5-ethyl-phenyl)-4- (3-methox- phenyl)-5-hydroxy-[1,2,4] triazole 138

3-(2,4-Dihydroxy- 5-ethyl-phenyl)-4- (naphthalen-1-yl)-5-hydroxy-[1,2,4] triazole 139

3-(2,4-Dihydroxy- 5-ethyl-phenyl)-4- (1-isopropyl- indol-3-yl)-5-hydroxy-[1,2,4] triazole 140

3-(2,4-Dihydroxy- 5-ethyl-phenyl)-4- (1-isopropyl- indol-4-yl)-5-amino-[1,2,4] triazole 141

3-(2,4-Dihydroxy- 5-ethyl-phenyl)-4- (3-methoxy- phenyl)-5-amino-[1,2,4] triazole 142

3-(2,4-Dihydroxy- 5-ethyl-phenyl)-4- (naphthalen-1-yl)- 5-amino-[1,2,4]triazole 143

3-(2-Hydroxy-5- ethyloxy-phenyl)- 4-(naphthalen-1- yl)-5-hydroxy-[1,2,4] triazole 144

3-(2-Hydroxy-5- isopropyl-phenyl)- 4-(naphthalen-1- yl)-5-hydroxy-[1,2,4] triazole 145

3-(2-Dihydroxy- phenyl)-4-(7- fluoro- naphthalen-1-yl)-5-hydroxy-[1,2,4] triazole 146

3-(2,4-Dihydroxy- phenyl)-4-(2,3- difluorophenyl)-5- hydroxy-[1,2,4]triazole 147

3-(2,4-Dihydroxy- phenyl)-4-[2-(1H- tetrazol-5-yl)- phenyl]-5-hydroxy-[1,2,4] triazole 148

3-(2,4-Dihydroxy- phenyl)-4- (benzothiazol-4- yl)-5-hydroxy- [1,2,4]triazole 149

3-(2,4-Dihydroxy- phenyl)-4-(9H- purin-6-yl)-5- hydroxy-[1,2,4] triazole150

3-(2,4-Dihydroxy- phenyl)-4-{4-[2- (morpholin-1-yl)- ethoxy]-phenyl}-5-hydroxy-[1,2,4] triazole 151

3-(2,4-Dihydroxy- phenyl)-4- cyclopentyl-5- hydroxy-[1,2,4] triazole 152

3-(2,4-Dihydroxy- phenyl)-4-phenyl- 5- (sulfamoylamino)- [1,2,4]triazole 153

3-(2,4-Dihydroxy- 5-methoxy- phenyl)-4- (naphthalene-1- yl)-5-ureido-[1,2,4] triazole 154

3-(2,4-Dihydroxy- 5-methoxy- phenyl)-4-(2,3- difluorophenyl)-5-ureido-[1,2,4] triazole 155

3-(2,4-Dihydroxy- 5-ethyl-phenyl)-4- (1-isopropyl- indol-4-yl)-5-ureido-[1,2,4] triazole 156

3-(2,4-Dihydroxy- 5-ethyl-phenyl)-4- (quinolin-5-yl)-5- ureido-[1,2,4]triazole 157

3-(2,4-Dihydroxy- 5-methoxy- phenyl)-4- (naphthalene-1- yl)-5-carbamoyloxy- [1,2,4] triazole 158

3-(2,4-Dihydroxy- 5-ethyl-phenyl)-4- (3-trifluoromethyl- phenyl)-5-carbamoyloxy- [1,2,4] triazole 159

3-(2,4-Dihydroxy- 5-ethyl-phenyl)-4- (1-methyl-indol-4- yl)-5-carbamoyloxy- [1,2,4] triazole 160

3-(2,4-Dihydroxy- 5-methoxy- phenyl)-4-(8- methoxy-quinolin- 5-yl)-5-carbamoyloxy- [1,2,4] triazole 161

3-(2,4-Dihydroxy- 5-isopropyl- phenyl)-4-(3- methyl-quinolin-5- yl)-5-carbamoxyamino- [1,2,4] triazole 162

3-(2,4-Dihydroxy- phenyl)-4-(1- methyl-2-chloro- indol-4-yl)-5-carbamoyloxy- [1,2,4] triazole 163

3-(2,4-Dihydroxy- 5-methoxy- phenyl)-4-[2,5-di- (trifluoromethyl)-phenyl]-5- carbamoyloxy- [1,2,4] triazole 164

3-(2,4-Dihydroxy- 5-methoxy- phenyl)-4-(3- trifluoromethyl- phenyl)-5-(sulfamoylamino)- [1,2,4] triazole 165

3-(2,4-Dihydroxy- 5-methoxy- phenyl)-4- (naphthalene-1- yl)-5-(sulfamoylamino)- [1,2,4] triazole 166

3-(2,4-Dihydroxy- 5-methoxy- phenyl)-4-(1- isopropyl- benzoimidazol-4-yl)-5- (sulfamoylamino)- [1,2,4] triazole 167

3-(2,4-Dihydroxy- 5-methoxy- phenyl)-4-(3- isopropylphenyl)- 5-(thiocarboxyamino)- [1,2,4] triazole 168

3-(2,4-Dihydroxy- 5-methoxy- phenyl)-4-(3- isopropyloxy- phenyl)-5-(sulfamoyloxy)- [1,2,4] triazole 169

3-(2,4-Dihydroxy- 5-methoxy- phenyl)-4- (naphthalene-1- yl)-5-(sulfamoyloxy)- [1,2,4] triazole 170

3-(2,4-Dihydroxy- 5-methoxy- phenyl)-4-(1- isopropyl- benzoimidazol-4-yl)-5- (sulfamoyloxy)- [1,2,4] triazole 171

3-(2-Hydroxy-4- ethoxycarbonyoxy- 5-methoxy- phenyl)-4-(1- isopropyl-benzoimidazol-4- yl)-5-hydroxy-[1,2,4] triazole 172

3-(2-Hydroxy-4- ethoxycarbonyoxy- 5-ethyl-phenyl)- 4-(naphthalin-2-yl)-5-hydroxy-[1,2,4] triazole 173

3-[2-Hydroxy-4- (dimethyl- carbamoyoxy)-5- ethyl-phenyl]-4-(naphthalin-2- yl)-5-hydroxy-[1,2,4] triazole 174

3-[2-Hydroxy-4- (dimethyl- carbomoyoxy)-5- chloro-phenyl]-4-(quinolin-5-yl)-5- mercapto-[1,2,4] triazole 175

3-[2-Hydroxy-4- (dimethyl- carbomoyoxy)-5- ethyl-phenyl]-4-(2,3-difluoro- phenyl)-5- mercapto-[1,2,4] triazole 176

3-[2-Hydroxy-4- isobutyryloxy-5- ethyl-phenyl]-4- (1-methyl-benzo-imidazol-4-yl)-5- hydroxy-[1,2,4] triazole 177

3-(2,4-Dihydroxy- 5-methoxy- phenyl)-4- (naphthalen-1-yl)- 5-mercapto-[1,2,4] triazole 178

3-(2,4-Dihydroxy- 5-ethyl-phenyl)-4- (5-hydroxy- naphthalen-1-yl)-5-mercapto- [1,2,4] triazole 179

3-(2,4-Dihydroxy- phenyl)-4- (naphthalen-1- ylmethyl)-5-mercapto-[1,2,4] triazole 180

3-(2-Hydroxy-4- methoxyphenyl)-4- (naphthalen-1-yl)- 5-mercapto- [1,2,4]triazole 181

3-(2,4-Dihydroxy- phenyl)-4- (biphenyl-3-yl)-5- mercapto-[1,2,4]triazole 182

3-(2,4-Dihydroxy- phenyl)-4-(2- methyl-5- hydroxymethyl- phenyl)-5-mercapto-[1,2,4] triazole 183

3-(2,4-Dihydroxy- phenyl)-4-(1- dimethylcarbamoyl- indol-4-yl)-5-mercapto-[1,2,4] triazole 184

3-(2,4,5- Trihydroxy- phenyl)-4- (naphthalene-1- yl)-5-mercapto- [1,2,4]triazole 185

3-(2,4-Dihydroxy- 5-ethyl-phenyl)-4- (2,3-dimethyl- indol-5-yl)-5-mercapto- [1,2,4] triazole 186

3-(2,4-Dihydroxy- 5-ethyl-phenyl)-4- (3-t-butyl-4- methoxy-phenyl)-5-mercapto- [1,2,4] triazole 187

3-(2,4-Dihydroxy- 5-ethyl-phenyl)-4- (1-ethyl-1H- benzoimidazol-4-yl)-5-mercapto- [1,2,4] triazole, HCl salt 188

3-(2,4-Dihydroxy- 5-ethyl-phenyl)-4- (1-isopropyl-7- methoxy-indol-4-yl)-5-mercapto- [1,2,4] triazole 189

3-(2,4-Dihydroxy- 5-cyclopropyl)- phenyl)-4- yl)-5-mercapto- [1,2,4]triazole 190

3-(2,4-dihydroxy- 5-ethyl-phenyl)-4- (1-propyl-indol-4- yl)-5-mercapto-[1,2,4] triazole 191

3-(2,4-dihydroxy- 5-ethyl-phenyl)-4- (1-acetyl-2,3- dimethyl-indol-5-yl)-5-mercapto- [1,2,4] triazole 192

3-(2,4-dihydroxy- 5-ethyl-phenyl)-4- (2-methyl-3-ethyl- benzimidazol-5-yl)-5-mercapto- [1,2,4] triazole 193

3-(2,4-dihydroxy- 5-ethyl-phenyl)-4- (1-ethyl-2-methyl- benzimidazol-5-yl)-5-mercapto- [1,2,4] triazole 194

3-(2,4-dihydroxy- 5-ethyl-phenyl)-4- (1-propyl-2,3- dimethyl-indol-5-yl)-5-mercapto- [1,2,4] triazole 195

3-(2,4-dihydroxy- 5-ethyl-phenyl)-4- (N-methyl- tetrahydrocarbozol-7-yl)-5- mercapto-[1,2,4] triazole 196

3-(2,4-dihydroxy- 5-ethyl-phenyl)-4- (N-methyl- cyclononan[a]indol-5-yl)-5- mercapto-[1,2,4] triazole 197

3-(2,4-dihydroxy- 5-ethyl-phenyl)-4- (1-n-butyl-indol-4- yl)-5-mercapto- [1,2,4] triazole 198

3-(2,4-dihydroxy- 5-ethyl-phenyl)-4- (1-n-pentyl-indol-4-yl)-5-mercapto- [1,2,4] triazole 199

3-(2,4-dihydroxy- 5-ethyl-phenyl)-4- (1-n-hexyl-indol- 4-yl)-5-mercapto-[1,2,4] triazole 200

3-(2,4-dihydroxy- 5-cyclopropyl)- phenyl)-4-(1-(1- methylcyclopropyl)-indol-4-yl)-5- mercapto- [1,2,4] triazole 201

3-(2,4-dihydroxy- 5-cyclopropyl)- phenyl)-4-(1- isopropyl-7-methoxy)-indol-4- yl)-5-mercapto- [1,2,4] triazole 202

3-(2,4-dihydroxy- 5-cyclopropyl)- phenyl)-4-(1,2,3- trimethyl-indol-5-yl)-5-mercapto- [1,2,4] triazole 203

3-(2,4-dihydroxy- 5-ethyl-phenyl)-4- (1-isopropyl-7- methoxy-indol-4-yl)-5-mercapto- [1,2,4] triazole disodium salt 204

3-(2,4-dihydroxy- 5-tert-butyl- phenyl)-4-(1- isopropyl-7-methoxy-indol-4- yl)-5-mercapto- [1,2,4] triazole 205

3-(2,4-dihydroxy- 5-cyclopropyl- phenyl)-4-(1- propyl-7-methoxy-indol-4- yl)-5-mercapto- [1,2,4] triazole 206

3-(2,4-dihydroxy- 5-ethyl-phenyl)-4- (1-methyl-3-ethyl- indol-5-yl)-5-mercapto- [1,2,4] triazole disodium salt 207

3-(2,4-dihydroxy- 5-ethyl-phenyl)-4- (1,3-dimethyl- indol-5-yl)-5-mercapto- [1,2,4] triazole 208

3-(2,4-dihydroxy- 5-isopropyl- phenyl)-4-(1- isopropyl-7-methoxy-indol-4- yl)-5-mercapto- [1,2,4] triazole 209

3-(2,4-dihydroxy- 5-ethyl-phenyl)-4- (1-methyl-3- isopropyl-indol-5-yl)-5-mercapto- [1,2,4] triazole 210

3-(2,4-dihydroxy- 5-ethyl-phenyl)-4- (N-ethyl-carbozol-7-yl)-5-mercapto- [1,2,4] triazole 211

3-(2,4-dihydroxy- 5-ethyl-phenyl)-4- (1-isopropyl-7- hydroxy-indol-4-yl)-5-mercapto- [1,2,4] triazole 212

3-(2,4-dihydroxy- 5-ethyl-phenyl)-4- (1-isopropyl-7- ethoxy-indol-4-yl)-5-mercapto- [1,2,4] triazole 213

3-(2,4-dihydroxy- 5-ethyl-phenyl)-4- (1,2-dimethyl- indol-5-yl)-5-mercapto-[1,2,4] triazole 214

3-(2,4-dihydroxy- 5-ethyl-phenyl)-4- (N-methyl-indol- 5-yl)-5-mercapto-[1,2,4] triazole 215

3-(2,4-dihydroxy- 5-ethyl-phenyl)-4- (2-methyl-7- methoxy-benzofuran-4-yl) 5-mercapto- [1,2,4] triazole 216

3-(2,4-dihydroxy- 5-ethyl-phenyl)-4- (benzofuran-5-yl) 5-mercapto-[1,2,4] triazole 217

3-(2,4-dihydroxy- 5-ethyl-phenyl)-4- (2-methyl-1,3- benzoxaz-5-yl)-5-mercapto- [1,2,4] triazole 218

3-(2,4-dihydroxy- 5-isopropyl- phenyl)-4-(1,3- dimethyl-indol-5-yl)-5-mercapto- [1,2,4] triazole 219

3-(2,4-dihydroxy- 5-cyclopropyl- phenyl)-4-(1,3- dimethyl-indol-5-yl)-5-mercapto- [1,2,4] triazole 220

3-(2,4-dihydroxy- 5-ethyl-phenyl)-4- (1,3-dimethyl- indol-5-yl)-5-hydroxy-[1,2,4] triazole 221

3-(2,4-dihydroxy- 5-isopropyl- phenyl)-4-(N- methyl-indol-5-yl)-5-mercapto- [1,2,4] triazole 222

3-(2,4-dihydroxy- 5-isopropyl- phenyl)-4-(1,2- dimethyl-indol-5-yl)-5-mercapto- [1,2,4] triazole 223

3-(2,4-dihydroxy- 5-isopropyl- phenyl)-4-(1,3- dimethyl-indol-5-yl)-5-hydroxy- [1,2,4] triazole 224

3-(2,4-dihydroxy- 5-cyclopropyl- phenyl)-4-(1- methyl-indol-5-yl)-5-mercapto- [1,2,4] triazole 225

3-(2,4-dihydroxy- 5-isopropyl- phenyl)-4-(1H- indol-5- yl)-5-mercapto-[1,2,4] triazole 226

3-(2,4-dihydroxy- 5-isopropyl- phenyl)-4-(1- methyl-indol-5-yl)-5-hydroxy- [1,2,4] triazole 227

3-(2,4-dihydroxy- 5-isopropyl- phenyl)-4-(1- ethyl-indol-5-yl)-5-mercapto- [1,2,4] triazole 228

3-(2,4-dihydroxy- 5-isopropyl- phenyl)-4-(1- propyl-indol-5-yl)-5-mercapto- [1,2,4] triazole 229

3-(2,4-dihydroxy- 5-isopropyl- phenyl)-4-(1- methyl-2- trifluoromethyl-benzimidazol-5- yl)-5-mercapto- [1,2,4] triazole 230

3-(2,4-dihydroxy- 5-isopropyl- phenyl)-4-(1- methyl-indazol-5-yl)-5-mercapto- [1,2,4] triazole 231

3-(2,4-dihydroxy- 5-isopropyl- phenyl)-4-(1- methyl-indazol-6-yl)-5-mercapto- [1,2,4] triazole 232

3-(2,4-dihydroxy- 5-isopropyl- phenyl)-4-(1- isopropyl-indol-4-yl)-5-hydroxy- [1,2,4] triazole 233

3-(2,4-dihydroxy- 5-isopropyl- phenyl)-4-(1,3- benzodiaxol-5-yl)-5-mercapto- [1,2,4] triazole 234

3-(2,4-dihydroxy- 5-isopropyl- phenyl)-4-(indan- 5-yl)-5-mercapto-[1,2,4] triazole 235

3-(2,4-dihydroxy- 5-isopropyl- phenyl)-4-(2- methyl-indazol-6-yl)-5-mercapto- [1,2,4] triazole 236

3-(2,4-dihydroxy- 5-ethyl-phenyl)-4- (3-oxo- benzo[1,4]oxazin-6-yl-(5-mercapto- [1,2,4] triazole 237

3-(2,4-dihydroxy- 5-ethyl-phenyl)-4- (2-oxo-1,3- dihydro-benzoimidazol-5- yl)-5-mercapto- [1,2,4] triazole 238

3-(2,4-dihydroxy- 5-isopropyl- phenyl)-4-(2H- benzo[1,4]oxazin-6-yl)-5-mercapto- [1,2,4] triazole 239

4-Ethyl-6-[5- mercapto-4-(1- methyl-2,3- dihydro-1H-indol- 5-yl)-4H-[1,2,4]triazol-3- yl]-benzene-1,3- diol 240

5-(3-(5-ethyl-2,4- dihydroxyphenyl)- 5-mercapto-4H- 1,2,4-triazol-4-yl)indolin-2-one 241

5-(3-(5-ethyl-2,4- dihydroxyphenyl)- 5-mercapto-4H- 1,2,4-triazol-4-yl)-1H- benzo[d]imidazol- 2(3H)-one 242

5-(3-(5-ethyl-2,4- dihydroxyphenyl)- 5-mercapto-4H- 1,2,4-triazol-4-yl)-1-methylindolin-2- one 243

4-isopropyl-6-(5- mercapto-4-(4- propyl-3,4- dihydro-2H- benzo[b][1,4]oxazin-6-yl)- 4H-1,2,4- triazol-3- yl)benzene-1,3- diol 244

6-(3-(5-ethyl-2,4- dihydroxyphenyl)- 5-mercapto-4H- 1,2,4-triazol-4-yl)-2H- benzo[b][1,4] oxazin-3(4H)-one 245

6-(3-(5-ethyl-2,4- dihydroxyphenyl)- 5-mercapto-4H- 1,2,4-triazol-4-yl)-3- methylbenzo[d] thiazol-2(3H)-one 246

6-(3-(5-ethyl-2,4- dihydroxyphenyl)- 5-mercapto-4H- 1,2,4-triazol-4-yl)benzo[d] thiazol- 2(3H)-one

Preferred compounds of the invention are those compounds that can form atautomeric structure as shown below and as exemplified by the tautomericstructures shown in Table 1:

Similarly, prodrugs, i.e. compounds which can be metabolized orhydrolyzed in vivo to a compound of the present invention areencompassed by the present description. For example, the followingembodiments of a compound of the present invention can be produced invivo in the following reaction:

where R₂₀₀ is R₂, R₅ or R₁₈.

One skilled in the art will understand that other hydrolyzableprotecting groups can be employed with the compounds of the presentinvention to obtain prodrugs encompassed by the present description.

Without wishing to be bound by any theory, it is believed that thecompounds of the invention preferentially bind to Hsp90 in thetautomeric form shown above, and thereby inhibit the activity of Hsp90.

C. Methods for Making Compounds of the Invention

Compounds of the invention can be obtained via standard, well-knownsynthetic methodology, see e.g., March, J. Advanced Organic Chemistry;Reactions Mechanisms, and Structure, 4th ed., 1992.

Compounds of the invention can also be made as in the followingprovisional applications: 60/808,376, filed May 25, 2006; 60/808,342,filed May 25, 2006; and 60/808,375, filed May 25, 2006, which areincorporated by reference herein in their entirety.

In particular, compounds of the invention can be obtained by heating ahydrazide (A) with an isocyanate (X₁₄═O), isothiocyanate, (X₁₄═S) orcarbodiimide (X₁₄═NR₇) (B) in an alcohol to form intermediate (C).Intermediate (C) can be cyclized to form a triazole core (D) by heatingit in an aqueous solution which includes about 2 molar equivalents ofNaOH (see Scheme I below). Starting materials useful for preparingcompounds of the invention and intermediates therefore, are commerciallyavailable or can be prepared from commercially available materials usingknown synthetic methods and reagents. For example, a hydrazide can beprepared by reacting an ester (such as 2,4-dihydroxybenzoic acid methylester) or acid chloride with hydrazine. Isocyanates and isothiocyanates(X₁₄ is O or S, respectively) can be formed in a number of ways fromcompounds that have a primary amine group. For example, a primary aminecan be reacted with phosgene or thiophosgene to form an isocyanate or anisothiocyanate, respectively. Alternatively, a cyanate or thiocyanateion can be reacted with an alkyl halide to form an alkyl isocyanate oran alkyl isothiocyanate. In addition, a isothiocyanate can be preparedby reacting a diazonium salt with a thiocyanate ion. Carbodiimides (X₁₄is NR₇) can be prepared by dehydration of ureas using a dehydrationagent such as tosyl chloride in pyridine, POCl₃, PCl₅, P₂O₅-pyridine,and Ph₃PBr₂-Et₃N. Other methods of preparing isocyanates,thioisocyanates, and carbodiimides can be found in March, J. AdvancedOrganic Chemistry; Reactions Mechanisms, and Structure, 4th ed., 1992,the entire teachings of which are incorporated by reference.

Compounds represented by formulas (IV) and (V) can be made in ananalogous fashion as compounds depicted in Scheme I.

Reactive functional groups can be protected during one or more reactionstep, then deprotected to restore the original functionality. Examplesof suitable protecting groups for hydroxyl groups include benzyl,methoxymethyl, allyl, trimethylsilyl, tert-butyldimethylsilyl, acetate,and the like. Examples of suitable amine protecting groups includebenzyloxycarbonyl, tert-butoxycarbonyl, tert-butyl, benzyl andfluorenylmethyloxy-carbonyl (Fmoc). Examples of suitable thiolprotecting groups include benzyl, tert-butyl, acetyl, methoxymethyl andthe like. Other suitable protecting groups are well known to those ofordinary skill in the art and include those found in T. W. Greene,Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981.

An alternative method of preparing the compounds of the invention isshown in Scheme II. In this method, an aryl, heteroaryl, cycloalkyl, oralkyl amine compound (i) is stirred at about room temperature with athiocarbonyl (ii) which has two leaving groups, L₁ and L₂, such asimidazole-1-yl groups, to form compound (iii). Typically, thethiocarbonyl compound is present in a slight molar excess of about 1.05eq. to about 1.3 eq. compared with compound (i). Compound (iii) is thencombined with a hydrazide compound (iv) in a solvent and heated to about50° C. to about 100° C. for about 0.5 to 5 hrs to form compound (v).Typically, compound (iii) and compound (iv) can be present in aboutequal molar ratio or a slight excess of compound (iii), such as about1.01 to about 1.1 molar eq. of compound (iii) compare to compound (iv).Compound (v) can then be cyclized to form a triazole compound of theinvention (vi) by suspending it in aqueous solution containing about 2molar eq. of NaOH and heating the solution to about 75° C. to about 110°C. for about 0.5 hr to about 2 hrs. Typically, the NaOH solutioncontaining compound (v) is degassed before heating by bubbling an inertgas, such as nitrogen or argon, through it.

In one embodiment, ring A of the compounds of the invention is a2,4-dihydroxyphenyl group. In this embodiment, it is sometimes desirableto prepare a prodrug by protecting the 4-hydroxy group with a moietythat can be hydrolyzed in vivo. Protection of 4-hydroxy group isexpected to improve the circulating half-life of compound compounds ofthe invention. In addition, it is desirable that a group added to the4-hydroxy group increase the water solubility of the compounds of theinvention. In one embodiment, 4-methyl-piperizine-1-carbamoyl group isused to protect the 4-hydroxy group (see Scheme III). In thisembodiment, a compound of the invention, such as compound (E), istreated with about one molar equivalents of4-methyl-piperizine-1-carbonyl chloride (F) in the presence of a base toform compound (G) in which the 4-hydroxy group is protected.Alternatively, the mercapto group can be protected first by reactingcompound (E) with about one molar equivalent of acyl chloride in thepresence of a base to form intermediate (H). Intermediate (H) can thembe reacted with about one molar equivalent of4-methyl-piperizine-1-carbonyl chloride (F) in the presence of a base,then the acetyl group can be removed by treatment with a mild acid toform compound (G).

Another prodrug of compounds of the invention can be formed by additionof a phosphate group to the 4-hydroxy group (Scheme IV). In thisembodiment, a compound of the invention, such as compound (E), istreated with about one molar equivalent of diisopropyl phosphoramidousacid di-t-butyl ester in the presence of tetrazole to yield compound(J). The phosphorous group is then oxidized with m-CPBA to form aphosphoric acid di-t-butyl ester group of compound K. The t-butyl groupsare then hydrolyzed with trifluoroacetic acid (TFA) to yield aphosphoric acid group or compound L.

D. Uses of Compounds of the Invention

The present invention provides methods for treating, reducing orinhibiting angiogenesis in a subject in need thereof, comprisingadministering to the subject an effective amount of a compoundrepresented by formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII),(IX), (X), or any embodiment thereof, or a compound shown in Table 1.

In one aspect, compounds of the invention are used in combination withone or more other therapeutic agents. In one aspect, compounds of theinvention are used in combination with one or more other anti-angiogenicagents.

In another aspect, the invention provides methods of reducing, blocking,occluding, or otherwise disrupting blood flow in neovasculature,comprising contacting the neovasculature with an effective amount of acompound represented by formula (I), (II), (III), (IV), (V), (VI),(VII), (VIII), (IX), (X), or any embodiment thereof, or a compound shownin Table 1. In one aspect, the neovasculature is in a subject and bloodflow in the neovasculature is reduced, blocked, occluded, or otherwisedisrupted in the subject by administering to the subject an effectiveamount of a compound represented by formula (I), (II), (III), (IV), (V),(VI), (VII), (VIII), (IX), (X), or any embodiment thereof, or a compoundshown in Table 1. In one aspect, the subject is human.

2. Agents Useful in Combination with the Compounds of the Invention

Anti-angiogenesis agents that can be co-administered with the compoundsof the invention include Dalteparin, Suramin, ABT-510, Combretastatin A4Phosphate, Lenalidomide, LY317615 (Enzastaurin), Soy Isoflavone(Genistein; Soy Protein Isolate), Thalidomide, AMG-706, Anti-VEGFAntibody (Bevacizumab; Avastin™), AZD2171, Bay 43-9006 (Sorafenibtosylate), PI-88, PTK787/ZK 222584 (Vatalanib), SU11248 (Sunitinibmalate), VEGF-Trap, XL184, ZD6474, ATN-161, EMD 121974 (Cilenigtide),Celecoxib, Angiostatin, Endostatin, Regranex, Apligraf, Paclitaxel,tetracyclines, clarithromycin, lasix, captopril, aspirin, Vitamin D3analogs, retinoids, Imiquomod, Interferon alfa2a, Minocycline, copperpeptide containing dressings, Lucentis™, ATG002, Pegaptanib Sodium,Tryptophanyl-tRNA synthetase, squalamine lactate, anecortave acetate,AdPEDF, AG-013958, JSM6427, TG100801, Veglin, ascorbic acid ethers (andtheir analogs), and Pamidronate.

Anti-cancer agents that can be employed in combination with thecompounds of the invention include Taxol™, also referred to as“paclitaxel”, is a well-known anti-cancer drug which acts by enhancingand stabilizing microtubule formation, and analogs of Taxol™, such asTaxotere™. Compounds that have the basic taxane skeleton as a commonstructure feature, have also been shown to have the ability to arrestcells in the G2-M phases due to stabilization or inhibition ofmicrotubules. Other anti-cancer agents that can be employed incombination with compounds of the invention include Avastin, Adriamycin,Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin;acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine;ambomycin; ametantrone acetate; aminoglutethimide; amsacrine;anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa;azotomycin; batimastat; benzodepa; bicalutamide; bisantrenehydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate;brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone;caracemide; carbetimer; carboplatin; carmustine; carubicinhydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin;cladribine; crisnatol mesylate; cyclophosphamide; cytarabine;dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin;dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicinhydrochloride; droloxifene; droloxifene citrate; dromostanolonepropionate; duazomycin; edatrexate; eflornithine hydrochloride;elsamitrucin; enloplatin; enpromate; epipropidine; epirubicinhydrochloride; erbulozole; esorubicin hydrochloride; estramustine;estramustine phosphate sodium; etanidazole; etoposide; etoposidephosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide;floxuridine; fludarabine phosphate; fluorouracil; flurocitabine;fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride;hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine;interleukin II (including recombinant interleukin II, or rIL2),interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferonalfa-n3; interferon beta-Ia; interferon gamma-Ib; iproplatin; irinotecanhydrochloride; lanreotide acetate; letrozole; leuprolide acetate;liarozole hydrochloride; lometrexol sodium; lomustine; losoxantronehydrochloride; inasoprocol; maytansine; mechlorethamine hydrochloride;megestrol acetate; melengestrol acetate; melphalan; menogaril;mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; initindomide; mitocarcin; mitocromin; mitogillin;mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride;mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran;pegaspargase; peliomycin; pentamustine; peplomycin sulfate;perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride;pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride;semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantronehydrochloride; temoporfin; teniposide; teroxirone; testolactone;thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifenecitrate; trestolone acetate; triciribine phosphate; trimetrexate;trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracilmustard; uredepa; vapreotide; verteporfin; vinblastine sulfate;vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate;vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate;vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin;zinostatin; zorubicin hydrochloride.

Other anti-cancer drugs that can be employed in combination with thecompounds of the invention include: 20-epi-1,25 dihydroxyvitamin D3;5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol;adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine;amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine;anagrelide; anastrozole; andrographolide; angiogenesis inhibitors;antagonist D; antagonist G; antarelix; antidorsalizing morphogeneticprotein-1; antiandrogen, prostatic carcinoma; antiestrogen;antineoplaston; antisense oligonucleotides; aphidicolin glycinate;apoptosis gene modulators; apoptosis regulators; apurinic acid;ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane;atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron;anatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat;BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactamderivatives; beta-alethine; betaclamycin B; betulinic acid; bFGFinhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide;bistratene A; bizelesin; breflate; bropirimine; budotitane; buthioninesulfoximine; calcipotriol; calphostin C; camptothecin derivatives;canarypox IL-2; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimatole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron;doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen;ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur;epirubicin; epristeride; estramustine analogue; estrogen agonists;estrogen antagonists; etanidazole; etoposide phosphate; exemestane;fadrozole; fazarabine; fenretinide; filgrastim; finasteride;flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinarnide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin;pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine;pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin;pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen-binding protein; sizofiran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; virixaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatinstimalamer. Preferred anti-cancer drugs are 5-fluorouracil andleucovorin.

Other chemotherapeutic agents that can be employed in combination withthe compounds of the invention include but are not limited to alkylatingagents, antimetabolites, natural products, or hormones. Examples ofalkylating agents useful for the treatment or prevention of T-cellmalignancies in the methods and compositions of the invention includebut are not limited to, nitrogen mustards (e.g., mechloroethamine,cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g.,busulfan), nitrosoureas (e.g., carmustine, lomustine, etc.), ortriazenes (decarbazine, etc.). Examples of antimetabolites useful forthe treatment or prevention of T-cell malignancies in the methods andcompositions of the invention include but are not limited to folic acidanalog (e.g., methotrexate), or pyrimidine analogs (e.g., Cytarabine),purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).Examples of natural products useful for the treatment or prevention ofT-cell malignancies in the methods and compositions of the inventioninclude but are not limited to vinca alkaloids (e.g., vinblastin,vincristine), epipodophyllotoxins (e.g., etoposide), antibiotics (e.g.,daunorubicin, doxorubicin, bleomycin), enzymes (e.g., L-asparaginase),or biological response modifiers (e.g., interferon alpha).

Examples of alkylating agents that can be employed in combination withthe compounds of the invention include but are not limited to, nitrogenmustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil,melphalan, etc.), ethylenimine and methylmelamines (e.g.,hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan),nitrosoureas (e.g., carmustine, lomustine, semustine, streptozocin,etc.), or triazenes (decarbazine, etc.). Examples of antimetabolitesuseful for the treatment or prevention of cancer in the methods andcompositions of the invention include but are not limited to folic acidanalog (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil,floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine,thioguanine, pentostatin). Examples of natural products useful for thetreatment or prevention of cancer in the methods and compositions of theinvention include but are not limited to vinca alkaloids (e.g.,vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide,teniposide), antibiotics (e.g., actinomycin D, daunorubicin,doxorubicin, bleomycin, plicamycin, mitomycin), enzymes (e.g.,L-asparaginase), or biological response modifiers (e.g., interferonalpha). Examples of hormones and antagonists useful for the treatment orprevention of cancer in the methods and compositions of the inventioninclude but are not limited to adrenocorticosteroids prednisone),progestins (e.g., hydroxyprogesterone caproate, megestrol acetate,medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol,ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g.,testosterone propionate, fluoxymesterone), antiandrogen (e.g.,flutamide), gonadotropin releasing hormone analog (e.g., leuprolide).Other agents that can be used in the methods and compositions of theinvention for the treatment or prevention of cancer include platinumcoordination complexes (e.g., cisplatin, carboblatin), anthracenedione(e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methylhydrazine derivative (e.g., procarbazine), adrenocortical suppressant(e.g., mitotane, aminoglutethimide).

Examples of anti-cancer agents which act by arresting cells in the G2-Mphases due to stabilization or inhibition of microtubules and which canbe used in combination with the compounds of the invention includewithout limitation the following marketed drugs and drugs indevelopment: Erbulozole (also known as R-55104), Dolastatin 10 (alsoknown as DLS-10 and NSC-376128), Mivobulin isethionate (also known asCI-980), Vincristine, NSC-639829, Discodermolide (also known asNVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins(such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such asSpongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4,Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, andSpongistatin 9), Cemadotin hydrochloride (also known as LU-103793 andNSC-D-669356), Epothilones (such as Epothilone A, Epothilone B,Epothilone C (also known as desoxyepothilone A or dEpoA), Epothilone D(also referred to as KOS-862, dEpoB, and desoxyepothilone B), EpothiloneE, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide,16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705),21-hydroxyepothilone D (also known as Desoxyepothilone F and dEpoF),26-fluoroepothilone), Auristatin PE (also known as NSC-654663),Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known asLS-4577), LS-4578 (Pharmacia, also known as LS-477-P), LS-4477(Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), Vincristinesulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known asWS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy ofSciences), BSF-223651 (BASF, also known as ILX-651 and LU-223651),SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97(Armad/Kyowa Haldco), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko),IDN-5005 (Indena), Cryptophycin 52 (also known as LY-355703), AC-7739(Ajinomoto, also known as AVE-8063A and CS-39.HCl), AC-7700 (Ajinomoto,also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCl, and RPR-258062A),Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known asNSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 andTI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261 andWHI-261), H10 (Kansas State University), H16 (Kansas State University),Oncocidin A1 (also known as BTO-956 and DIME), DDE-313 (Parker HughesInstitute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute),SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU(Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569),Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asia Medica),A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai Schoolof Medicine, also known as MF-191), TMPN (Arizona State University),Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, Inanocine(also known as NSC-698666), 3-IAABE (Cytoskeleton/Mt. Sinai School ofMedicine), A-204197 (Abbott), T-607 (Tularik, also known as T-900607),RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin,Desaetyleleutherobin, Isoeleutherobin A, and Z-Eleutherobin),Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica),D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350(Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott),Diozostatin, (−)-Phenylahistin (also known as NSCL-96F037), D-68838(Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris,also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286(also known as SPA-110, trifluoroacetate salt) (Wyeth), D-82317(Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphatesodium, BPR-0Y-007 (National Health Research Institutes), and SSR-250411(Sanofi).

E. Compositions and Methods for Administering Therapies

The present invention provides compositions for the treatment orprevention of angiogenesis related disorders, such as maculardegeneration. In a specific embodiment, a composition comprises one ormore compounds of the invention, or a pharmaceutically acceptable salt,solvate, clathrate, hydrate or prodrug thereof. In another embodiment, acomposition of the invention comprises one or more prophylactic ortherapeutic agents other than a compound of the invention, or apharmaceutically acceptable salt, solvate, clathrate, hydrate, prodrugthereof. In another embodiment, a composition of the invention comprisesone or more compounds of the invention, or a pharmaceutically acceptablesalt, solvate, clathrate, hydrate or prodrug thereof, and one or moreother prophylactic or therapeutic agents. In another embodiment, thecomposition comprises a compound of the invention, or a pharmaceuticallyacceptable salt, solvate, clathrate, hydrate, or prodrug thereof, and apharmaceutically acceptable carrier, diluent or excipient.

In a preferred embodiment, a composition of the invention is apharmaceutical composition or a single unit dosage form. Pharmaceuticalcompositions and dosage forms of the invention comprise one or moreactive ingredients in relative amounts and formulated in such a way thata given pharmaceutical composition or dosage form can be used to treator prevent angiogenesis related disorders, such as macular degeneration.Preferred pharmaceutical compositions and dosage forms comprise acompound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII),(IX), (X), or Table 1, or a pharmaceutically acceptable prodrug, salt,solvate, clathrate, hydrate, or prodrug thereof, optionally incombination with one or more additional active agents.

A pharmaceutical composition of the invention is formulated to becompatible with its intended route of administration. Examples of routesof administration include, but are not limited to, parenteral, e.g.,intravenous, intradermal, subcutaneous, oral (e.g., inhalation),intranasal, transdermal (topical), transmucosal, and rectaladministration. In a specific embodiment, the composition is formulatedin accordance with routine procedures as a pharmaceutical compositionadapted for intravenous, subcutaneous, intramuscular, oral, intranasalor topical administration to human beings. In a preferred embodiment, apharmaceutical composition is formulated in accordance with routineprocedures for subcutaneous administration to human beings.

Single unit dosage forms of the invention are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), or transdermal administration to a patient. Examples ofdosage forms include, but are not limited to: tablets; caplets;capsules, such as soft elastic gelatin capsules; cachets; troches;lozenges; dispersions; suppositories; ointments; cataplasms (poultices);pastes; powders; dressings; creams; plasters; solutions; patches;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; and sterile solids (e.g., crystalline or amorphous solids)that can be reconstituted to provide liquid dosage forms suitable forparenteral administration to a patient.

The composition, shape, and type of dosage forms of the invention willtypically vary depending on their use. For example, a dosage formsuitable for mucosal administration may contain a smaller amount ofactive ingredient(s) than an oral dosage form used to treat the sameindication. This aspect of the invention will be readily apparent tothose skilled in the art. See, e.g., Remington's Pharmaceutical Sciences(1990) 18th ed., Mack Publishing, Easton, Pa.

Typical pharmaceutical compositions and dosage forms comprise one ormore excipients. Suitable excipients are well known to those skilled inthe art of pharmacy, and non-limiting examples of suitable excipientsare provided herein. Whether a particular excipient is suitable forincorporation into a pharmaceutical composition or dosage form dependson a variety of factors well known in the art including, but not limitedto, the way in which the dosage form will be administered to a patient.For example, oral dosage forms such as tablets may contain excipientsnot suited for use in parenteral dosage forms.

The suitability of a particular excipient may also depend on thespecific active ingredients in the dosage form. For example, thedecomposition of some active ingredients can be accelerated by someexcipients such as lactose, or when exposed to water. Active ingredientsthat comprise primary or secondary amines (e.g., N-desmethylvenlafaxineand N,N-didesmethylvenlafaxine) are particularly susceptible to suchaccelerated decomposition. Consequently, this invention encompassespharmaceutical compositions and dosage forms that contain little, ifany, lactose. As used herein, the term “lactose-free” means that theamount of lactose present, if any, is insufficient to substantiallyincrease the degradation rate of an active ingredient. Lactose-freecompositions of the invention can comprise excipients that are wellknown in the art and are listed, for example, in the U.S. Pharmacopia(USP) SP (XXI)/NF (XVI). In general, lactose-free compositions compriseactive ingredients, a binder/filler, and a lubricant in pharmaceuticallycompatible and pharmaceutically acceptable amounts. Preferredlactose-free dosage forms comprise active ingredients, microcrystallinecellulose, pre-gelatinized starch, and magnesium stearate.

This invention further encompasses anhydrous pharmaceutical compositionsand dosage forms comprising active ingredients, since water canfacilitate the degradation of some compounds. For example, the additionof water (e.g., 5%) is widely accepted in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. See, e.g., Jens T. Carstensen (1995) Drug Stability: Principles &Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 379-80. In effect, water andheat accelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine are preferablyanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are preferably packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

The invention further encompasses pharmaceutical compositions and dosageforms that comprise one or more compounds that reduce the rate by whichan active ingredient will decompose. Such compounds, which are referredto herein as “stabilizer” include, but are not limited to, antioxidantssuch as ascorbic acid, pH buffers, or salt buffers.

1) Oral Dosage Forms

Pharmaceutical compositions of the invention that are suitable for oraladministration can be presented as discrete dosage forms, such as, butare not limited to, tablets (e.g., chewable tablets), caplets, capsules,and liquids (e.g., flavored syrups). Such dosage forms containpredetermined amounts of active ingredients, and may be prepared bymethods of pharmacy well known to those skilled in the art. Seegenerally, Remington's Pharmaceutical Sciences (1990) 18th ed., MackPublishing, Easton, Pa.

Typical oral dosage forms of the invention are prepared by combining theactive ingredient(s) in an admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. For example, excipients suitablefor use in oral liquid or aerosol dosage forms include, but are notlimited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms, in which case solidexcipients are employed. If desired, tablets can be coated by standardaqueous or nonaqueous techniques. Such dosage forms can be prepared byany of the methods of pharmacy. In general, pharmaceutical compositionsand dosage forms are prepared by uniformly and intimately admixing theactive ingredients with liquid carriers, finely divided solid carriers,or both, and then shaping the product into the desired presentation ifnecessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms of theinvention include, but are not limited to, binders, fillers,disintegrants, and lubricants. Binders suitable for use inpharmaceutical compositions and dosage forms include, but are notlimited to, corn starch, potato starch, or other starches, gelatin,natural and synthetic gums such as acacia, sodium alginate, alginicacid, other alginates, powdered tragacanth, guar gum, cellulose and itsderivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropylmethyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystallinecellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Onespecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103J and Starch 1500LM.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions of the invention istypically present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Disintegrants are used in the compositions of the invention to providetablets that disintegrate when exposed to an aqueous environment.Tablets that contain too much disintegrant may disintegrate in storage,while those that contain too little may not disintegrate at a desiredrate or under the desired conditions. Thus, a sufficient amount ofdisintegrant that is neither too much nor too little to detrimentallyalter the release of the active ingredients should be used to form solidoral dosage forms of the invention. The amount of disintegrant usedvaries based upon the type of formulation, and is readily discernible tothose of ordinary skill in the art. Typical pharmaceutical compositionscomprise from about 0.5 to about 15 weight percent of disintegrant,preferably from about 1 to about 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, agar-agar,alginic acid, calcium carbonate, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, other starches, pre-gelatinizedstarch, other starches, clays, other algins, other celluloses, gums, andmixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, andmixtures thereof. Additional lubricants include, for example, a syloidsilica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore,Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co.of Plano, Tx.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants are typically used in an amount of less than about 1 weightpercent of the pharmaceutical compositions or dosage forms into whichthey are incorporated.

2) Controlled Release Dosage Forms

Active ingredients of the invention can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active ingredients of the invention. The invention thusencompasses single unit dosage forms suitable for oral administrationsuch as, but not limited to, tablets, capsules, gelcaps, and capletsthat are adapted for controlled-release.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased patient compliance.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

A particular extended release formulation of this invention comprises atherapeutically or prophylactically effective amount of a compound offormula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), orTable 1, or a pharmaceutically acceptable salt, solvate, hydrate,clathrate, or prodrug thereof, in spheroids which further comprisemicrocrystalline cellulose and, optionally,hydroxypropylmethyl-cellulose coated with a mixture of ethyl celluloseand hydroxypropylmethylcellulose. Such extended release formulations canbe prepared according to U.S. Pat. No. 6,274,171, the entirely of whichis incorporated herein by reference.

A specific controlled-release formulation of this invention comprisesfrom about 6% to about 40% a compound of formula (I), (II), (III), (IV),(V), (VI), (VII), (VIII), (IX), (X), or Table 1, or a pharmaceuticallyacceptable salt, solvate, hydrate, clathrate, or prodrug thereof, byweight, about 50% to about 94% microcrystalline cellulose, NF, byweight, and optionally from about 0.25% to about 1% by weight ofhydroxypropyl-methylcellulose, USP, wherein the spheroids are coatedwith a film coating composition comprised of ethyl cellulose andhydroxypropylmethylcellulose.

3) Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. Becausetheir administration typically bypasses patients' natural defensesagainst contaminants, parenteral dosage forms are preferably sterile orcapable of being sterilized prior to administration to a patient.Examples of parenteral dosage forms include, but are not limited to,solutions ready for injection, dry products ready to be dissolved orsuspended in a pharmaceutically acceptable vehicle for injection,suspensions ready for injection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage forms ofthe invention are well known to those skilled in the art. Examplesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms of the invention.

4) Transdermal, Topical, and Mucosal Dosage Forms

Transdermal, topical, and mucosal dosage forms of the invention include,but are not limited to, ophthalmic solutions, sprays, aerosols, creams,lotions, ointments, gels, solutions, emulsions, suspensions, or otherforms known to one of skill in the art. See, e.g., Remington'sPharmaceutical Sciences (1980 & 1990) 16th and 18th eds., MackPublishing, Easton, Pa. and Introduction to Pharmaceutical Dosage Forms(1985) 4th ed., Lea & Febiger, Philadelphia. Dosage forms suitable fortreating mucosal tissues within the oral cavity can be formulated asmouthwashes or as oral gels. Further, transdermal dosage forms include“reservoir type” or “matrix type” patches, which can be applied to theskin and worn for a specific period of time to permit the penetration ofa desired amount of active ingredients.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide transdermal, topical, and mucosal dosageforms encompassed by this invention are well known to those skilled inthe pharmaceutical arts, and depend on the particular tissue to which agiven pharmaceutical composition or dosage form will be applied. Withthat fact in mind, typical excipients include, but are not limited to,water, acetone, ethanol, ethylene glycol, propylene glycol,butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil,and mixtures thereof to form lotions, tinctures, creams, emulsions, gelsor ointments, which are non-toxic and pharmaceutically acceptable.Moisturizers or humectants can also be added to pharmaceuticalcompositions and dosage forms if desired. Examples of such additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences (1980 & 1990) 16th and 18th eds., MackPublishing, Easton, Pa.

Depending on the specific tissue to be treated, additional componentsmay be used prior to, in conjunction with, or subsequent to treatmentwith active ingredients of the invention. For example, penetrationenhancers can be used to assist in delivering the active ingredients tothe tissue. Suitable penetration enhancers include, but are not limitedto: acetone; various alcohols such as ethanol, oleyl, andtetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such aspolyvinylpyrrolidone; Kollidon grades (Povidone, Polyvidone); urea; andvarious water-soluble or insoluble sugar esters such as Tween 80(polysorbate 80) and Span 60 (sorbitan monostearate).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, mayalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

5) Dosage & Frequency of Administration

The amount of the compound or composition of the invention which will beeffective in the prevention, treatment, management, or amelioration ofan angiogenesis related disorder, such as macular degeneration, or oneor more symptoms thereof, will vary with the nature and severity of thedisease or condition, and the route by which the active ingredient isadministered. The frequency and dosage will also vary according tofactors specific for each patient depending on the specific therapy(e.g., therapeutic or prophylactic agents) administered, the severity ofthe disorder, disease, or condition, the route of administration, aswell as age, body, weight, response, and the past medical history of thepatient. Effective doses may be extrapolated from dose-response curvesderived from in vitro or animal model test systems. Suitable regimentscan be selected by one skilled in the art by considering such factorsand by following, for example, dosages reported in the literature andrecommended in the Physician's Desk Reference (57th ed., 2003).

Exemplary doses of a small molecule include milligram or microgramamounts of the small molecule per kilogram of subject or sample weight(e.g., about 1 microgram per kilogram to about 500 milligrams perkilogram, about 100 micrograms per kilogram to about 5 milligrams perkilogram, or about 1 microgram per kilogram to about 50 micrograms perkilogram).

In general, the recommended daily dose range of a compound of theinvention for the conditions described herein lie within the range offrom about 0.01 mg to about 1000 mg per day, given as a singleonce-a-day dose preferably as divided doses throughout a day. In oneembodiment, the daily dose is administered twice daily in equallydivided doses. Specifically, a daily dose range should be from about 5mg to about 500 mg per day, more specifically, between about 10 mg andabout 200 mg per day. In managing the patient, the therapy should beinitiated at a lower dose, perhaps about 1 mg to about 25 mg, andincreased if necessary up to about 200 mg to about 1000 mg per day aseither a single dose or divided doses, depending on the patient's globalresponse. It may be necessary to use dosages of the active ingredientoutside the ranges disclosed herein in some cases, as will be apparentto those of ordinary skill in the art. Furthermore, it is noted that theclinician or treating physician will know how and when to interrupt,adjust, or terminate therapy in conjunction with individual patientresponse.

Different therapeutically effective amounts may be applicable fordifferent diseases or disorders, as will be readily known by those ofordinary skill in the art. Similarly, amounts sufficient to prevent,manage, treat or ameliorate angiogenesis related disorders, butinsufficient to cause, or sufficient to reduce, adverse effectsassociated with the compounds of the invention are also encompassed bythe above described dosage amounts and dose frequency schedules.Further, when a patient is administered multiple dosages of a compoundof the invention, not all of the dosages need be the same. For example,the dosage administered to the patient may be increased to improve theprophylactic or therapeutic effect of the compound or it may bedecreased to reduce one or more side effects that a particular patientis experiencing.

In a specific embodiment, the dosage of the composition of the inventionor a compound of the invention administered to prevent, treat, manage,or ameliorate angiogenesis related disorders, such as maculardegeneration, or one or more symptoms thereof in a patient is 150 μg/kg,preferably 250 μg/kg, 500 μg/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 25 mg/kg,50 mg/kg, 75 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, or 200 mg/kg ormore of a patient's body weight. In another embodiment, the dosage ofthe composition of the invention or a compound of the inventionadministered to prevent, treat, manage, or ameliorate angiogenesisrelated disorders, such as macular degeneration, or one or more symptomsthereof in a patient is a unit dose of 0.1 mg to 20 mg, 0.1 mg to 15 mg,0.1 mg to 12 mg, 0.1 mg to 10 mg, 0.1 mg to 8 mg, 0.1 mg to 7 mg, 0.1 mgto 5 mg, 0.1 to 2.5 mg, 0.25 mg to 20 mg, 0.25 to 15 mg, 0.25 to 12 mg,0.25 to 10 mg, 0.25 to 8 mg, 0.25 mg to 7 mg, 0.25 mg to 5 mg, 0.5 mg to2.5 mg, 1 mg to 20 mg, 1 mg to 15 mg, 1 mg to 12 mg, 1 mg to 10 mg, 1 mgto 8 mg, 1 mg to 7 mg, 1 mg to 5 mg, or 1 mg to 2.5 mg.

The dosages of prophylactic or therapeutic agents other than compoundsof the invention, which have been or are currently being used toprevent, treat, manage, or proliferative disorders, such as cancer, orone or more symptoms thereof can be used in the combination therapies ofthe invention. Preferably, dosages lower than those which have been orare currently being used to prevent, treat, manage, or ameliorate aproliferative disorders, or one or more symptoms thereof, are used inthe combination therapies of the invention. The recommended dosages ofagents currently used for the prevention, treatment, management, oramelioration of a proliferative disorders, such as cancer, or one ormore symptoms thereof, can obtained from any reference in the artincluding, but not limited to, Hardman et al., eds., 1996, Goodman &Gilman's The Pharmacological Basis Of Basis Of Therapeutics 9^(th) Ed,Mc-Graw-Hill, New York; Physician's Desk Reference (PDR) 57^(th) Ed.,2003, Medical Economics Co., Inc., Montvale, N.J., which areincorporated herein by reference in its entirety.

In certain embodiments, when the compounds of the invention areadministered in combination with another therapy, the therapies (e.g.,prophylactic or therapeutic agents) are administered less than 5 minutesapart, less than 30 minutes apart, 1 hour apart, at about 1 hour apart,at about 1 to about 2 hours apart, at about 2 hours to about 3 hoursapart, at about 3 hours to about 4 hours apart, at about 4 hours toabout 5 hours apart, at about 5 hours to about 6 hours apart, at about 6hours to about 7 hours apart, at about 7 hours to about 8 hours apart,at about 8 hours to about 9 hours apart, at about 9 hours to about 10hours apart, at about 10 hours to about 11 hours apart, at about 11hours to about 12 hours apart, at about 12 hours to 18 hours apart, 18hours to 24 hours apart, 24 hours to 36 hours apart, 36 hours to 48hours apart, 48 hours to 52 hours apart, 52 hours to 60 hours apart, 60hours to 72 hours apart, 72 hours to 84 hours apart, 84 hours to 96hours apart, or 96 hours to 120 hours part. In one embodiment, two ormore therapies (e.g., prophylactic or therapeutic agents) areadministered within the same patent visit.

In certain embodiments, one or more compounds of the invention and oneor more other the therapies (e.g., prophylactic or therapeutic agents)are cyclically administered. Cycling therapy involves the administrationof a first therapy (e.g., a first prophylactic or therapeutic agents)for a period of time, followed by the administration of a second therapy(e.g., a second prophylactic or therapeutic agents) for a period oftime, followed by the administration of a third therapy (e.g., a thirdprophylactic or therapeutic agents) for a period of time and so forth,and repeating this sequential administration, i.e., the cycle in orderto reduce the development of resistance to one of the agents, to avoidor reduce the side effects of one of the agents, and/or to improve theefficacy of the treatment.

In certain embodiments, administration of the same compound of theinvention may be repeated and the administrations may be separated by atleast 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days,2 months, 75 days, 3 months, or 6 months. In other embodiments,administration of the same prophylactic or therapeutic agent may berepeated and the administration may be separated by at least at least 1day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2months, 75 days, 3 months, or 6 months.

In a specific embodiment, the invention provides a method of preventing,treating, managing, or ameliorating a proliferative disorders, such ascancer, or one or more symptoms thereof, said methods comprisingadministering to a subject in need thereof a dose of at least 150 μg/kg,preferably at least 250 μg/kg, at least 500 μg/kg, at least 1 mg/kg, atleast 5 mg/kg, at least 10 mg/kg, at least 25 mg/kg, at least 50 mg/kg,at least 75 mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150mg/kg, or at least 200 mg/kg or more of one or more compounds of theinvention once every day, preferably, once every 2 days, once every 3days, once every 4 days, once every 5 days, once every 6 days, onceevery 7 days, once every 8 days, once every 10 days, once every twoweeks, once every three weeks, or once a month.

F. Other Embodiments

The compounds of the invention may be used as research tools (forexample, to evaluate the mechanism of action of new drug agents, toisolate new drug discovery targets using affinity chromatography, asantigens in an ELISA or ELISA-like assay, or as standards in in vitro orin vivo assays). These and other uses and embodiments of the compoundsand compositions of this invention will be apparent to those of ordinaryskill in the art.

The invention is further defined by reference to the following examplesdescribing in detail the preparation of compounds of the invention. Itwill be apparent to those skilled in the art that many modifications,both to materials and methods, may be practiced without departing fromthe purpose and interest of this invention. The following examples areset forth to assist in understanding the invention and should not beconstrued as specifically limiting the invention described and claimedherein. Such variations of the invention, including the substitution ofall equivalents now known or later developed, which would be within thepurview of those skilled in the art, and changes in formulation or minorchanges in experimental design, are to be considered to fall within thescope of the invention incorporated herein.

EXAMPLES

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wis., USA). ¹H-NMR and ¹³C-NMRspectra were recorded on a Varian 300 MHz NMR spectrometer. Significantpeaks are tabulated in the order: δ (ppm): chemical shift, multiplicity(s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br s,broad singlet), coupling constant(s) in Hertz (Hz) and number ofprotons.

Example 1 Synthesis of Compound 76

The hydrazide (M) (1.45 g, 7.39 mmol) and the isothiocyanate (N) (1.59g, 7.39 mmol) were dissolved in ethanol (20 ml) with heating. When thestarting materials were dissolved the solution was allowed to cool toroom temperature and a precipitate formed. This precipitate was filteredthen washed with ether to provide the intermediate (P) as a white solid(2.85 g, 97%). The intermediate (VII) (1.89 g, 4.77 mmol) was heated ina solution of sodium hydroxide (0.38 g, 9.54 mmol) in water (20 mL) at110° C. for 2 hours. The solution was allowed to cool to roomtemperature then acidified with conc. HCl. The resulting precipitate wasfiltered then washed with water (100 mL) and dried. The crude productwas recrystallized from ethanol to produce compound 76 as a white solid(1.4 g, 75%).

¹H NMR (DMSO-d₆) δ 9.43-9.53 (bs, 2H),8.11-8.16 (m, 1H), 7.47-7.55 (m,2H), 7.38 (d, J=8.1 Hz, 1H), 7.31-7.36 (m, 1H), 6.98 (d, J=8.1 Hz, 1H),6.71 (s, 1H), 6.17 (s, 1H), 3.98 (s, 3H), 2.17 (q, J=7.5 Hz, 2H), 0.73(t, J=7.5 Hz, 3H);

ESMS calculated for (C₂₁H₁₉N₃O₃S) 393.11; Found 394.1(M+1)⁺.

Example 2 Synthesis of Compound 124

3-(2,4-Dihydroxy-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole (505mg, 1.5 mmol), which is commercially available from Scientific Exchange,Inc., Center Ossipee, NH 03814, and Et₃N (0.84 ml, 6.0 mmol) in 15 mlCH₂Cl₂ were treated dropwise with ethyl isocyanate (360 mg, 5.0 mmol) at0° C. The mixture was then warmed to room temperature and stirred for 3h. The reaction mixture was diluted with CH₂Cl₂, washed with H₂O andsaturated brine, dried with Na₂SO₄, and concentrated in vacuo. Theresidue was chromatographed (Hexane/EtOAc 3:1) to give Compound 124 as awhite solid (480 mg, 58%).

¹H-NMR (CDCl₃) δ 10.13 (s, 1H), 7.96 (d, J=9.0 Hz, 2H), 7.61-7.57 (m,3H), 7.49-7.36(m, 2H), 7.01(s, 1H), 6.88 (d, J=8.4 Hz, 1H), 6.70 (d,J=8.4 Hz, 1H), 4.98-4.96(m, 2H), 3.56(q, J=7.2 Hz, J=12.6 Hz, 2H),3.28-3.10(m, 4H), 1.33(t, J=7.2 Hz, 3H), 1.13 (q, J=15.0 Hz, J=7.2 Hz,6H);

ESMS calculated for C₂₇H₂₈N₆O₅S: 548.18; Found: 549.1 (M+1)⁺.

Example 3 Synthesis of Compound 188

1-Benzenesulfonyl-7-methoxy-1H-indole (Q)

To a solution of 7-methoxyindole (1 eq) in DMF cooled in an ice bath wasadded NaH (60% dispersion in oil, 1.2 eq). The reaction was stirred for1 hr at room temperature then recooled in an ice bath. Benzenesulfonylchloride (1.1 eq) was added then the reaction was stirred for 2 hrs atroom temperature. Water/ethyl acetate were added and the ethyl acetatelayer was washed repeatedly (3×) with water. The ethyl acetate layer wasconcentrated and evaporated to dryness.

1-Benzenesulfonyl-7-methoxy-4-nitro-1H-indole (R)

To a solution of 1-benzenesulfonyl-7-methoxy-1H-indole (Q) (1 eq) indichloromethane cooled in an ice bath was added SiO₂—HNO₃ (2 wt eq) insmall portions. The reaction was stirred for 1 hr at room temperature.Activated carbon (2 wt eq) was added then the entire mixture was stirredfor 1 hr. The mixture was then filtered and evaporated to dryness.Separation of the isomers was achieved by column chromatography.

7-Methoxy-4-nitro-1H-indole (S)

To a solution of 1-benzenesulfonyl-7-methoxy-4-nitro-1H-indole (R) (1eq) in methanol was added a solution of sodium hydroxide (5 eq) inwater. The solution was heated to reflux for 3 hrs. Methanol was removedunder reduced pressure then water and ethyl acetate were added. Theethyl acetate layer separated and washed repeatedly (3×) with water. Theethyl acetate layer was concentrated and evaporated to dryness toproduce the desired product.

1-Isopropyl-7-methoxy-4-nitro-1H-indole (T)

To a solution of 7-methoxy-4-nitro-1H-indole (S) (1 eq) in DMF cooled inan ice bath was added NaH (60% dispersion in oil, 1.2 eq). The reactionwas stirred for 1 hr at room temperature then recooled in an ice bath.2-Iodopropane (1.1 eq) was added then the reaction was stirred for 2 hrsat room temperature. Water and ethyl acetate were added. The ethylacetate layer was separated and washed repeatedly (3×) with water. Theethyl acetate layer was concentrated then evaporated to dryness. Furtherpurification by column chromatography produced the pure desired product.

1-Isopropyl-7-methoxy-1H-indol-4-ylamine (U)

A solution of 1-isopropyl-7-methoxy-4-nitro-1H-indole (T) (1 eq) andpalladium 10% on activated carbon (0.1 wt eq) in methanol/ethyl acetate(1:1) was shaken on a Parr hydrogenation apparatus under hydrogen for 1hr. The reaction was then filtered through Celite and evaporated todryness to produce the desired product.

1-Isopropyl-4-isothiocyanato-7-methoxy-1H-indole (V)

To a solution of 1-isopropyl-7-methoxy-1H-indol-4-ylamine (U) (1 eq) indichloromethane was added 1,1′-thiocarbonyldiimidazole (1.2 eq). Thereaction was stirred for 2 hrs at room temperature then evaporated todryness. Further purification by column chromatography produced the puredesired product.

3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole(Compound 188)

5-Ethyl-2,4-dihydroxy-benzoic acid hydrazide (W) (1 eq) and1-isopropyl-4-isothiocyanato-7-methoxy-1H-indole (V) (1.01 eq) wereheated in ethanol (0.02 M based on isothiocyanate) at 80° C. for 1 hr.The solution was allowed to cool to room temperature overnight. Theresulting precipitate was filtered, washed with ether, dried and usedwithout further purification (yield 80%). The precipitate was suspendedin aqueous NaOH solution (2 eq NaOH) and nitrogen was bubbled throughthis suspension for 10 min. The reaction was then heated to 110° C. for1 hr under a nitrogen atmosphere then allowed to cool to roomtemperature. Neutralisation with conc. HCl produced a white precipitatewhich was filtered and washed with water. Repeated recrystallisationfrom EtOH/water produced the desired product (purity >95%, yield 50-70%)

¹H-NMR (DMSO-d₆) δ (ppm), 9.52 (s, 1H), 9.42 (s, 1H), 7.40 (d, J=3.3 Hz,1H), 6.82 (d, J=8.4 Hz, 1H), 6.61 (s, 1H), 6.20 (s, 1H), 6.05 (d, J=3.3Hz, 1H), 5.30 (qn, J=6.6 Hz, 1H), 3.89 (s, 3H), 2.14 (q, J=7.5 Hz, 2H),1.41-1.47(m, 6H), 0.68 (t, J=7.5 Hz, 3H);

ESMS CALCULATED. FOR C₂₂H₂₄N₄O₃S: 424.16; FOUND: 425.1 (M+1)⁺.

Example 4 Synthesis of Compound 223

2,4-Dimethoxy-5-isopropylbenzoic acid (2.24 g, 10.0 mmol, 1.00 equiv.)in 50 mL CH₂Cl₂ at room temperature was treated with (COCl)₂ (1.40 g,11.0 mmol, 1.10 equiv.) and catalytic amount of DMF (0.1 mL) for 1 hour.Solvent and excess (COCl)₂ were removed in vacuo. The residue wasdissolved in 100 mL CH₂Cl₂, and treated with 1,3-dimethyl-5-aminoindole(1.60 g, 10.0 mmol, 1.00 equiv.) and triethylamine (1.55 g, 15.0 mmol,1.50 equiv.) at 0° C. for one hour. Aqueous workup and removal ofsolvent gave a light brown solid which was washed with ether to yieldoff-white solid (2.28 g, 6.22 mmol, 62%).

¹H NMR (CDCl₃) δ (ppm) 9.78 (br s, 1H), 8.21 (s, 1H), 8.09 (d, J=2.1 Hz,1H), 7.31 (dd, J=8.7 Hz, 2.1 Hz, 1H), 7.22 (d, J=8.7 Hz, 1H), 6.82 (s,1H), 6.50 (s, 1H), 4.09 (s, 3H), 3.92 (s, 3H), 3.73 (s, 3H), 3.26 (hept,J=6.9 Hz, 1H), 2.32 (s, 3H), 1.24 (d, J=6.9 Hz, 6H).

The off-white solid obtained above was treated with Lawesson's reagent(1.51 g, 3.74 mmol, 0.6 equiv.) in 50 mL toluene at 110° C. for threehours. Toluene was removed on rotary evaporator and vacuum pump, and theresidue was treated with hydrazine (anhydrous, 3.0 g, 94 mmol, 15.0equiv.) in 20 mL dioxane at 80° C. for 30 minutes. The reaction mixturewas extracted with ethyl acetate and water to remove excess hydrazine.The organic layer was dried over MgSO₄, and filtered to remove dryingagent. Carbodiimidazole (CDI) (3.02 g, 18.7 mmol, 3.00 equiv.) was addedto the solution, and the solution was refluxed (65° C.) for 2 hours.Solvent was removed, and the residue was treated with 20 mL THF and 10mL NaOH (2M) to destroy excess CDI. Extraction with ethyl acetate(EtOAc) and water, followed by chromatography purification gave thedesired product3-(2,4-methoxy-5-isopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-hydroxy-[1,2,4]triazoleas light brown solid (2.20 g, 5.42 mmol, 87%).

¹H NMR (CDCl₃), δ (ppm) 9.63 (br s, 1H), 7.34 (d, J=2.1 Hz, 1H), 7.20(s, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.00 (dd, J=8.4 Hz, 2.1 Hz, 1H), 6.80(s, 1H), 6.19 (s, 1H), 3.76 (s, 3H), 3.69 (s, 3H), 3.40 (s, 3H), 3.15(hept, J=6.9 Hz, 1H), 2.20 (s, 3H), 1.10 (d, J=6.9 Hz, 6H).

3-(2,4-methoxy-5-isopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-hydroxy-[1,2,4]triazoleobtained above was treated with pyridine hydrochloride (12.53 g, 108.3mmol, 20.0 equiv.), NaI (0.812 g, 5.42 mmol, 1.0 equiv.) and 0.5 mLwater at 205° C. under nitrogen protection for 1 hour. The reactionmixture was treated with 200 mL water. The solid was collected byfiltration, washed with 3×20 mL water, and dissolved in 50 mL 2M NaOHsolution. The aqueous solution was extracted with 100 mL EtOAc, and theEtOAc layer was extracted with 2×20 mL 0.5M NaOH. EtOAc layer wasdiscarded. The aqueous layer were combined, neutralized with HCl to PHaround 5, and extracted with 3×100 mL EtOAc. The combined EtOAc layerwas diluted with 50 mL THF, dried over MgSO₄, and filtered throughsilica gel plug. Most of solvents were removed to form a slurry witharound 2 mL of solvent left. Solid was collected by filtration, washedwith 2 mL EtOAc, and dried. The desired product3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole(Compound 223) was obtained as an off-white solid (1.75 g, 4.63 mmol,85%).

¹H NMR (CD₃OD), δ (ppm) 7.46 (d, J=1.8 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H),7.04 (dd, J=8.4 Hz, 1.8 Hz, 1H), 7.02 (s, 1H), 6.53 (s, 1H), 6.26 (s,1H), 3.74 (s, 3H), 2.88 (sept, J=6.9 Hz, 1H), 2.24 (s, 3H), 0.62 (d,J=6.9 Hz, 6H);

ESMS calculated for C₂₁H₂₃N₄O₃: 378.1; Found: 379.1 (M+1)⁺.

The following compounds were prepared as described above in the sectionentitled “Methods of Making the Compounds of the Invention” and asexemplified in Examples 1 through 4.

Example 5 Compound 1

ESMS calcd for C₁₈H₁₃N₃OS: 319.1; Found: 320.0 (M+1)⁺.

Example 6 Compound 2

ESMS calcd for C₂₁H₁₉N₃O₄S: 409.11; Found: 410.0 (M+H)⁺.

Example 7 Compound 5

ESMS calcd for C₁₉H₁₅N₃O₂S: 365.08; Found: 266.0 (M+H)⁺.

Example 8 Compound 6

ESMS calcd for C₂₀H₁₇N₃O₂S: 379.10; Found: 380.0 (M+H)⁺.

Example 9 Compound 7

ESMS calcd for C₂₁H₁₉N₃O₂S: 393.11; Found: 394.0 (M+H)⁺.

Example 10 Compound 8

ESMS calcd for C₂₁H₁₉N₃O₃S: 393.11; Found: 394.0(M+H)⁺.

Example 11 Compound 9

ESMS calcd for C₂₁H₁₉N₃O₂S: 393.11; Found: 394.0 (M+H)⁺.

Example 12 Compound 13

¹H-NMR (DMSO-d₆) δ 9.65 (s, 1H), 9.57 (s, 1H), 7.50 (d, J=8.1 Hz, 1H),7.35 (d, J=3.3 Hz, 1H), 7.14 (t, J=7.8 Hz, 1H), 6.96 (d, J=7.5 Hz, 1H),6.88 (d, J=8.1 Hz, 1H), 6.09-6.11 (m, 2H), 6.01 (dd, J₁=2.1 Hz, J₂=8.1Hz, 1H), 4.13-4.22 (m, 2H), 1.36 (t, J=7.2 Hz, 3H);

ESMS calcd for C₁₈H₁₆N₄O₂S: 352.10; Found: 353.1 (M+1)⁺.

Example 13 Compound 14

¹NMR (DMSO-d₆) δ 9.72(s, 1H), 9.67(s, 1H), 7.04-7.01(m, 1H),6.83-6.78(m, 2H), 6.66-6.63(m, 1H), 6.20-6.19(m, 2H), 4.22(s, 4H);

ESMS calcd for C₁₆H₁₃N₃O₄S: 343.06; Found: 344.0 (M+1)⁺.

Example 14 Compound 15

ESMS calcd for C₁₅H₁₃N₃O₂S: 299.07; Found: 300.0 (M+H)⁺.

Example 15 Compound 16

ESMS calcd for C₁₅H₁₃N₃O₂S: 299.07; Found: 300.0 (M+H)⁺.

Example 16 Compound 17

ESMS calcd for C₁₄H₁₀ClN₃O₂S: 319.02; Found: 320.0 (M+H)⁺.

Example 17 Compound 18

ESMS calcd for C₁₄H₁₀ClN₃O₂S: 319.02; Found: 320.0 (M+H)⁺.

Example 18 Compound 19

ESMS calcd for C₁₄H₁₀ClN₃O₂S: 319.02; Found: 320.1 (M+H)⁺.

Example 19 Compound 20

ESMS calcd for C₁₅H₁₃N₃O₃S: 315.07; Found: 316.0 (M+H)⁺.

Example 20 Compound 21

ESMS calcd for C₁₅H₁₃N₃O₃S: 315.07; Found: 316.0 (M+H)⁺.

Example 21 Compound 22

ESMS calcd for C₁₅H₁₃N₃O₃S: 315.07; Found: 316.0 (M+H)⁺.

Example 22 Compound 23

ESMS calcd for C₁₄H₁₀FN₃O₂S: 303.05; Found: 304.0 (M+H)⁺.

Example 23 Compound 23

¹H NMR (DMSO-d₆) δ 9.69 (s, 1H), 9.65 (s, 1H), 7.16 (d, J=7.2 Hz, 1H),7.05 (t, J=7.2 Hz, 1H), 6.93 (d, J=8.1 Hz, 2H), 6.11-6.16 (m, 2H), 2.21(s, 3H), 1.89 (s, 3H);

ESMS Calcd C₁₆H₁₅N₃O₂S: 313.09, Found 314.1(M+1)⁺.

Example 24 Compound 24

ESMS calcd for C₁₆H₁₅N₃O₂S: 313.09; Found: 314.0 (M+H)⁺.

Example 25 Compound 25

¹H NMR (DMSO-d₆) δ 10.44 (m, 1H), 8.00-7.95 (m, 2H), 7.55-7.37 (m, 5H),6.61 (d, J=7.8 and 1.8 Hz, 1H), 6.51 (t, J=8.6 Hz, 1H), 6.41(d, J=10.8Hz, 1H);

ESMS calcd for C₁₈H₁₂FN₃OS: 337.07; Found: 338.0 (M+1)⁺.

Example 26 Compound 26

¹H NMR (DMSO-d₆) δ 9.57 (s, 1H), 7.99 (d, J=8.4 Hz, 1H), 7.96 (d, J=6.9Hz, 1H), 7.55-7.37 (m, 5H), 6.61 (d, J=8.1 Hz, 1H), 5.83 (d, J=2.1 Hz,1H), 5.73(dd, J=8.1 and 1.8 Hz, 1H), 5.24 (s, 2H);

ESMS calcd for C₁₈H₁₄N₄OS: 334.09; Found: 335.0 (M+1)⁺.

Example 27 Compound 27

ESMS calcd for C₁₈H₁₉N₃O₂S: 341.12; Found: 342.0 (M+H)⁺.

Example 28 Compound 28

ESMS calcd for C₁₆H₁₅N₃O₂S: 313.09; Found: 314.0 (M+H)⁺.

Example 29 Compound 29

ESMS calcd for C₁₆H₁₅N₃O₂S: 313.09; Found: 314.0 (M+H)⁺.

Example 30 Compound 30

ESMS calcd for C₁₆H₁₅N₃O₂S: 313.09; Found: 314.0 (M+H)⁺.

Example 31 Compound 31

ESMS calcd for C₁₄H₁₀FN₃O₂S: 303.05; Found: 304.0 (M+H)⁺.

Example 32 Compound 32

ESMS calcd for C₁₅H₁₃N₃O₂S: 331.04; Found: 332.0 (M+H)⁺.

Example 33 Compound 33

ESMS calcd for C₁₈H₁₃N₃O₂S: 335.07; Found: 336.0 (M+H)⁺.

Example 34 Compound 34

ESMS calcd for C₁₆H₁₅N₃O₂S: 313.09; Found: 314.0 (M+H)⁺.

Example 35 Compound 35

ESMS calcd for C₁₅H₁₂FN₃O₂S: 317.06; Found: 317.0 (M+H)⁺.

Example 36 Compound 36

ESMS calcd for C20H15N3O2S: 361.1; Found: 362.0 (M+1)⁺.

Example 37 Compound 37

¹H NMR (DMSO-d₆) δ 10.03 (s, 1H), 8.00-7.96 (m, 2H), 7.55-7.37 (m, 5H),7.00 (d, J=8.1 Hz, 1H), 6.20 (m, 2H), 3.57 (s, 3H);

ESMS calcd for C₁₉H₁₅N₃O₂S: 349.09; Found: 350.0 (M+1)⁺.

Example 38 Compound 38

ESMS calcd for C₁₄H₉Cl₂N₃O₂S: 352.98; Found: 353.9 (M+H)⁺.

Example 39 Compound 39

¹H NMR (DMSO-d₆) δ 9.74 (s, 1H), 9.63 (s, 1H), 8.14 (m, 1H), 7.52-7.48(m, 2H), 7.37 (d, J=8.4 Hz, 1H), 7.32 (m, 1H), 6.96 (d, =8.1 Hz, 1H),6.90 (d, =8.4 Hz, 1H), 6.08 (d, =1.9 Hz, 1H), 6.01 (d, =8.4 Hz, 1H),3.98 (s, 3H);

ESMS calcd for C₁₉H₁₅N₃O₃S: 365.08; Found: 366.0 (M+1)⁺.

Example 40 Compound 40

ESMS calcd for C₂₅H₁₆N₃O₂S: 409.09; Found: 410.0 (M+1)⁺.

Example 41 Compound 42

¹H NMR (DMSO-d₆) δ 9.75(s, 1H), 9.67(s, 1H), 7.08(s, 2H), 6.96-6.94(m,2H), 6.18-6.13(m, 2H), 2.72-2.50(m, 3H), 2.35-2.28(m, 1H), 1.64-1.60(m,4H);

ESMS calcd for C₁₈H₁₇N₃O₂S: 339.10; Found: 340.0 (M+1)⁺.

Example 42 Compound 43

ESMS calcd for C₂₂H₁₅N₃O₂S: 385.09; Found: 386.0 (M+1)⁺.

Example 43 Compound 44

ESMS calcd for C₂₀H₁₅N₃O₂S: 361.09; Found: 362.0 (M+1)⁺.

Example 44 Compound 45

ESMS calcd for C₁₉H₁₅N₃O₂S: 349.09; Found: 350.0 (M+1)⁺.

Example 45 Compound 46

ESMS calcd for C₁₉H₂₁N₃O₃S: 371.13; Found: 372.0 (M+1)⁺.

Example 46 Compound 47

ESMS calcd for C₂₂H₂₇N₃O₃S: 413.18; Found: 414.1 (M+1)⁺.

Example 47 Compound 48

ESMS calcd for C₁₈H₁₂ClN₃O₂S: 369.03; Found: 370.0 (M+H)⁺.

Example 48 Compound 49

¹H NMR (DMSO-d₆) δ 9.49 (s, 1H), 9.40 (s, 1H), 7.94-7.99 (m, 2H),7.38-7.56 (m, 5H), 6.70 (s, 1H), 6.13 (s, 1H), 2.12 (q, J=7.2 Hz, 2H),0.71 (t, J=7.2 Hz, 3H);

ESMS Calcd for C₂₀H₁₇N₃O₂S: 363.10, Found 364.1(M+1)⁺.

Example 49 Compound 50

ESMS calcd for C₂₀H₁₅N₃O₅S: 409.07; Found: 410.0 (M+H)⁺.

Example 50 Compound 51

ESMS calcd for C₁₈H₁₄N₄O₂S: 350.08; Found: 351.0 (M+H)⁺.

Example 51 Compound 52

ESMS calcd for C₁₇H₁₂N₄OS: 320.07; Found: 320.9 (M+H)⁺.

Example 52 Compound 53

¹H NMR (CDCl₃) δ 12.0 (br s, 1H), 9.87 (br s, 1H), 9.83 (br s, 1H), 7.97(d, J=8.1 Hz, 2H), 7.41-7.56 (m, 5H), 7.13 (d, J=1.5 Hz, 1H), 7.07 (d,J=8.7 Hz, 1H), 6.71 (dd, J=1.8 Hz, 8.1 Hz, 1H), 1.93 (s, 3H);

ESMS calcd for C₂₀H₁₇N₄O₂S: 376.1; Found: 377.0(M+1)⁺.

Example 53 Compound 56

ESMS calcd for C₁₆H₁₅N₃O₄S: 345.08; Found: 346.0 (M+1)⁺.

Example 54 Compound 57

ESMS calcd for C₁₈H₁₆N₄O₂S: 352.10; Found: 353.0 (M+1)⁺.

Example 55 Compound 61

¹H NMR (DMSO-d₆) δ 9.66(s, 1H), 9.60(s, 1H), 7.29-7.27(m, 1H),7.12-7-10(m, 2H), 7.03-7.00(m, 1H), 6.19-6.17(m, 2H), 1.18(s, 18H);

ESMS calcd for C₂₂H₂₇N₃O₂S: 397.18; Found: 398.1 (M+1)⁺.

Example 56 Compound 64

ESMS calcd for C₂₁H₁₅N₃O₃S: 389.08; Found: 390.0 (M+H)⁺.

Example 57 Compound 65

ESMS calcd for C₁₉H₁₃N₃O₄S: 379.06; Found: 380.0 (M+1)⁺.

Example 58 Compound 66

ESMS calcd for C₂₁H₁₈N₄O₃S: 406.11; Found: 407.0 (M+1)⁺.

Example 59 Compound 67

ESMS calcd for C₂₁H₁₉N₃O₃S: 393.11; Found: 394.0 (M+1)⁺.

Example 60 Compound 68

ESMS calcd for C₂₁H₁₉N₃O₃S: 393.11; Found: 394.0 (M+1)⁺.

Example 61 Compound 69

ESMS calcd for C₂₁H₁₉N₃O₃S: 393.11; Found: 394.0 (M+1)⁺.

Example 62 Compound 70

ESMS calcd for C₁₇H₁₂N₄O₂S: 336.07; Found: 337.0 (M+1)⁺.

Example 63 Compound 71

ESMS calcd for C₂₁H₁₉N₃O₃S: 393.11; Found: 394.0 (M+1)⁺.

Example 64 Compound 72

¹H NMR (DMSO-d₆) δ 10.3 (br s, 1H), 7.95-8.19 (m, 2H), 7.48-7.72 (m,5H), 7.17 (d, J=8.4 Hz, 1H), 6.44 (d, J=8.4 Hz, 1H), 5:95 (d, J=2.1 Hz,1H), 5.73 (dd, J=2.1 Hz, 8.4 Hz, 1H), 5.47 (br s, 1H), 3.62 (s, 3H);

ESMS calcd for C₁₉H₁₇N₄O₂S₂: 412.1; Found: 413.0(M+1)⁺.

Example 65 Compound 73

¹H NMR (DMSO-d₆) δ 9.37 (s, 1H), 8.94 (s, 1H), 7.94-7.98 (m, 2H),7.43-7.60 (m, 5H), 5.97 (s, 1H), 1.85 (s, 3H), 1.81 (s, 3H);

ESMS calcd for C₂₀H₁₈N₃O₂S: 363.1; Found: 364.0(M+1)⁺.

Example 66 Compound 74

ESMS calcd for C₂₁H₁₉N₃O₄S: 409.11; Found: 410.0 (M+H)⁺.

Example 67 Compound 75

¹H NMR (DMSO-d₆) δ 9.46 (s, 1H), 9.45 (s, 1H), 7.95-8.00 (m, 2H),7.38-7.56 (m, 5H), 6.65 (s, 1H), 6.15 (s, 1H), 2.07-2.14 (m, 2H),081-1.18 (m, 11H);

ESMS calcd for C₂₄H₂₆N₃O₂S: 419.1; Found: 420.1(M+1)⁺.

Example 68 Compound 76

ESMS calcd for C₂₁H₁₉N₃O₃S: 393.11; Found: 394.0 (M+H)⁺.

Example 69 Compound 77

ESMS calcd for C₂₁H₁₉N₃O₃S: 393.11; Found: 394.0 (M+H)⁺.

Example 70 Compound 78

¹H NMR (DMSO-d₆) δ 9.71 (s, 1H), 9.35 (s, 1H), 7.98-8.04 (m, 2H),7.50-7.62 (m, 5H), 6.58 (s, 1H), 2.15 (q, J=7.5 Hz, 2H), 0.58 (t, J=7.5Hz, 3H);

ESMS calcd for C₂₀H₁₇ClN₃O₂S: 397.0; Found: 398.0(M+1)⁺.

Example 71 Compound 79

ESMS calcd for C₁₉H₂₁N₃O₃S: 371.13; Found: 372.0 (M+H)⁺.

Example 72 Compound 80

ESMS calcd for C₂₁H₁₉N₃O₂S: 393.11; Found: 394.0 (M+H)⁺.

Example 73 Compound 81

ESMS calcd for C₂₀H₁₇N₃O₂S: 379.10; Found: 380.0 (M+H)⁺.

Example 74 Compound 82

ESMS calcd for C₂₁H₁₉N₃O₂S: 393.11; Found: 394.0 (M+H)⁺.

Example 75 Compound 83

ESMS calcd for C₂₀H₁₇N₃O₃S: 379.10; Found: 380.0 (M+H)⁺.

Example 76 Compound 84

ESMS calcd for C₂₀H₁₇N₃O₃S: 379.10; Found: 380.0 (M+H)⁺.

Example 77 Compound 85

ESMS calcd for C₁₉H₁₅N₃O₂S: 365.08; Found: 266.0 (M+H)⁺.

Example 78 Compound 86

¹H NMR (DMSO-d₆) δ 9.68 (s, 1H), 9.58 (s, 1H), 8.2 (dd, J=7.0 and 2.4Hz, 1H), 7.50 (m, 2H), 7.40 (tr, J=8.1 Hz, 1H), 7.32 (m, 1H), 6.97 (d,J=7.5 Hz, 1H), 6.95 (m, 1H), 6.89 (d, =8.4 Hz, 1H), 6.08 (d, =2.1 Hz,1H), 6.0 (dd, =7.4 and 2.1 Hz, 1H), 3.96 (s, 3H);

ESMS calcd for C₁₉H₁₅N₃O₃S: 365.08; Found: 366.0 (M+1)⁺.

Example 79 Compound 87

¹H NMR (MeOH-d₄) δ 8.25 (m, 1H), 7.96 (s, 1H), 7.46-7.44 (m, 2H), 7.26(d, J=8.4 Hz, 1H), 6.83 (d, J=8.1 Hz, 1H), 6.70 (d, J=8.7 Hz, 1H), 6.17(d, J=2.1 Hz, 1H), 5.98 (dd, J=8.4 and 2.4 Hz, 1H);

ESMS calcd for C₁₈H₁₃N₃O₃S: 351.07; Found: 352.0 (M+1)⁺.

Example 80 Compound 88

¹H-NMR (DMSO-d₆) δ 9.69 (s, 1H), 9.59 (s, 1H), 7.54 (d, J=8.1 Hz, 1H),7.46 (d, J=3 Hz, 1H), 7.14 (t, J=7.8 Hz, 1H), 6.97 (d, J=7.2 Hz, 1H),6.89 (d, J=8.7 Hz, 1H), 6.12-6.13 (m, 2H), 6.02 (dd, J₁=2.4 Hz, J₂=8.4Hz, 1H), 4.74 (qn, J=6.6 Hz, 1H), 1.40-1.46 (m, 6H);

ESMS calcd for C₁₉H₁₈N₄O₂S: 366.12; Found: 367.1 (M+1)⁺.

Example 81 Compound 89

ESMS calcd for C₂₂H₂₁N₃O₂S: 391.14; Found: 392.0 (M+H)⁺.

Example 82 Compound 90

¹H NMR (DMSO-d₆) δ 9.47 (s, 1H), 9.43 (s, 1H), 7.94-8.00 (m, 2H),7.39-7.57 (m, 5H), 6.68 (s, 1H), 6.15 (s, 1H), 2.05-2.15 (m, 2H),1.05-1.17 (m, 2H), 0.50 (t, J=7.5 Hz, 3H); ESMS calcd for C₂₁H₂₀N₃O₂S:377.1; Found: 378.0(M+1)⁺.

Example 83 Compound 91

¹H NMR (DMSO-d₆) δ 9.15 (s, 1H), 8.50 (s, 1H), 8.00-8.07 (m, 2H),7.47-7.63 (m, 5H), 6.27 (s, 1H), 2.06 (q, J=7.5 Hz, 2H), 1.93 (s, 3H),0.45 (t, J=7.5 Hz, 3H);

ESMS calcd for C₂₁H₂₀N₃O₂S: 377.1; Found: 378.0(M+1)⁺.

Example 84 Compound 93

ESMS calcd for C₁₆H₁₅N₃O₄S: 345.08; Found: 346.0 (M+H)⁺.

Example 85 Compound 95

ESMS calcd for C₁₆H₁₂N₄O₂S: 324.07; Found: 325.0 (M+H)⁺.

Example 86 Compound 96

ESMS calcd for C₁₉H₁₈N₄O₃S: 382.11; Found: 383.0 (M+H)⁺.

Example 87 Compound 98

ESMS calcd for C₁₇H₁₂N₄O₂S: 336.07; Found: 337.0 (M+H)⁺.

Example 88 Compound 99

ESMS calcd for C₁₉H₁₃N₃O₄S: 379.06; Found: 379.9 (M+H)⁺.

Example 89 Compound 100

¹H-NMR (DMSO-d₆) δ 9.52 (s, 1H), 9.42 (s, 1H), 7.56 (d, J=8.7 Hz, 1H),7.49 (d, J=3.3 Hz, 1H), 7.14 (t, J=7.5 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H),6.61 (s, 1H), 6.21 (s, 1H), 6.14 (dd, J=3.3 Hz, 1H), 4.76 (qn, J=6.6 Hz,1H), 2.14 (q, J=7.5 Hz, 2H), 1.41-1.47 (m, 6H), 0.66 (t, J=7.5 Hz, 3H);

ESMS calcd for C₂₁H₂₂N₄O₂S: 394.15; Found: 395.1 (M+1)⁺.

Example 90 Compound 101

ESMS calcd for C₁₉H₁₇N₅O₃S: 395.11; Found: 396.0 (M+H)⁺.

Example 91 Compound 102

ESMS calcd. for C₁₉H₂₀N₅O₂S: 381.1; Found: 382.0 (M+1)⁺.

Example 92 Compound 103

¹H NMR (DMSO-d₆) δ 9.48 (s, 1H), 9.38 (s, 1H), 7.29(d, J=8.4 Hz, 1H),7.25(d, J=1.8 Hz, 1H), 6.85-6.89 (m, 2H), 6.18 (s, 1H), 3.61 (s, 3H),2.30 (s, 3H), 2.29 (q, J=7.5 Hz, 2H), 2.09 (s, 3H), 0.94 (t, J=7.5 Hz,3H);

ESMS calcd for C₂₁H₂₃N₄O₂S: 394.1; Found: 395.0(M+1)⁺.

Example 93 Compound 104

ESMS calcd for C₁₉H₁₅N₃O₃S: 365.08; Found: 366.0 (M+H)⁺.

Example 94 Compound 106

ESMS calcd for C₂₀H₁₇N₄O₂S: 377.1; Found: 378.0(M+H)⁺.

Example 95 Compound 107

ESMS calcd for C₁₈H₁₃ClN₃O₂S: 369.0; Found: 370.0(M+H)⁺.

Example 96 Compound 116

¹H NMR (DMSO-d₆) δ 7.98-7.56 (m, 2H), 7.55-7.30 (m, 6H), 6.43 (dd, J=8.1and 1.8 Hz, 1H), 6.29 (m, 1H), 3.65 (s, 3H), 3.16 (s, 3H);

ESMS calcd for C₂₀H₁₇N₃O₂S: 363.10; Found: 364.0 (M+1)⁺.

Example 97 Compound 117

¹H-NMR (CDCl₃) δ 7.83(d, J=8.1 Hz, 2H), 7.48-7.34(m, 4H), 7.28-7.20(m,1H), 6.99 (d, J=1.8 Hz, 1H), 6.80(d, J=8.7 Hz, 1H), 6.62-6.58(m, 1H),2.94(s, 3H), 2.89(s, 3H), 2.84(s, 3H), 2.81(s, 3H), 2.75-2.69(m, 6H);

ESMS calcd for C₂₇H₂₈N₆O₅S: 548.18; Found: 549.2 (M+1)⁺.

Example 98 Compound 122

¹H-NMR (CDCl₃) δ 7.98(m, 2H), 7.60-7.55(m, 3H), 7.51-7.45(m, 1H),7.36-7.33(m, 1H), 6.98-6.97(m, 1H), 6.86(d, J=9.9 Hz, 1H), 6.70-6.67(m,1H), 2.86(s, 3H), 2.26(s, 3H), 2.21(s, 3H);

ESMS calcd for C₂₄H₁₉N₃O₅S: 461.10; Found: 462.0 (M+1)⁺.

Example 99 Compound 125

ESMS calcd for C₂₀H₁₇N₃O₃S: 379.10; Found: 380.0 (M+H)⁺.

Example 100 Compound 126

ESMS calcd for C₁₀H₁₁N₃O₂S: 237.06; Found: 238.0 (M+H)⁺.

Example 101 Compound 127

ESMS calcd for C₁₁H₁₃N₃O₂S: 251.07; Found: 252.0 (M+H)⁺.

Example 102 Compound 128

ESMS calcd for C₁₁H₁₃N₃O₂S: 251.07; Found: 252.0 (M+H)⁺.

Example 103 Compound 129

ESMS calcd for C₁₁H₁₁N₃O₂S: 249.06; Found: 250.0 (M+H)⁺.

Example 104 Compound 130

ESMS calcd for C₁₂H₁₅N₃O₂S: 265.09; Found: 266.0 (M+H)⁺.

Example 105 Compound 131

ESMS calcd for C₂₀H₁₅N₃O₄S: 393.08; Found: 394.1 (M+H)⁺.

Example 106 Compound 177

¹H NMR (DMSO-d₆) δ 9.34(s, 1H), 9.22 (s, 1H), 8.01-7.96 (m, 2H),7.58-7.44 (m, 5H), 6.56 (s, 1H), 6.14 (s, 1H), 3.29 (s, 3H);

ESMS calcd for C₁₉H₁₅N₃O₃S: 365.08; Found: 366.0(M+1)⁺.

Example 107 Compound 178

¹H NMR (DMSO-d₆) δ 10.29 (s, 1H), 9.49 (s, 1H), 9.42 (s, 1H), 8.16 (t,J=5.1 Hz, 1H), 7.45-7.43 (m, 2H), 7.26 (t, J=8.0 Hz, 1H), 6.84 (d, J=7.8Hz, 1H), 6.75 (d, J=8.7 Hz, 1H), 6.66 (s, 1H), 6.14 (s, 1H), 2.12 (q,J=7.5 Hz, 2H), 0.70 (t, J=7.2 Hz, 3H);

ESMS calcd for C₂₀H₁₇N₃O₃S: 379.10; Found: 379.9 (M+1)⁺.

Example 108 Compound 179

ESMS calcd for C₁₉H₁₅N₃O₂S: 349.09; Found: 350.0 (M+1)⁺.

Example 109 Compound 180

ESMS calcd for C₁₉H₁₅N₃O₂S: 349.09; Found: 350.0 (M+H)⁺.

Example 110 Compound 181

ESMS calcd for C20H15N3O2S: 361.09; Found: 362.0 (M+H)⁺.

Example 111 Compound 182

ESMS calcd for C₁₆H₁₅ N₃O₃S: 329.08; Found: 330.0 (M+H)⁺.

Example 112 Compound 183

ESMS calcd for C₂₀H₁₇N₃O₂S: 363.10; Found: 364.0 (M+H)⁺.

Example 113 Compound 184

ESMS calcd for C₁₈H₁₃N₃O₃S: 350.38; Found: 351.9(M+H)⁺.

Example 114 Compound 185

ESMS calcd. for C₂₀H₂₁N₄O₂S: 380.1; Found: 381.0 (M+1)⁺.

Example 115 Compound 187

ESMS calcd. for C₁₉H₂₀N₅O₂S: 381.1; Found: 382.0 (M+1)⁺.

Example 116 Compound 190

ESMS CALCD. FOR C₂₁H₂₂N₄O₂S: 394.15; FOUND: 395.0 (M+1)⁺.

Example 117 Compound 191

ESMS calcd. for C₂₂H₂₃N₄O₄S: 438.1; Found: 439.0 (M+1)⁺.

Example 118 Compound 192

ESMS calcd. for C₂₀H₂₂N₅O₂S: 395.1; Found: 396.0 (M+1)⁺.

Example 119 Compound 193

ESMS calcd. for C₂₀H₂₂N₅O₂S: 395.1; Found: 396.0 (M+1)⁺.

Example 120 Compound 194

ESMS calcd. for C₂₃H₂₇N₄O₂S: 422.1; Found: 423.0 (M+1)⁺.

Example 121 Compound 195

ESMS calcd. for C₂₃H₂₅N₄O₂S: 420.1; Found: 421.0 (M+1)⁺.

Example 122 Compound 196

ESMS calcd. for C₂₅H₂₉N₄O₂S: 448.1; Found: 449.3 (M+1)⁺.

Example 123 Compound 197

ESMS calcd. for C₂₂H₂₄N₄O₂S: 408.16; Found: 409.2 (M+1)⁺.

Example 124 Compound 198

ESMS calcd. for C₂₃H₂₆N₄O₂S: 422.18; Found: 423.3 (M+1)⁺.

Example 125 Compound 199

ESMS calcd. for C₂₄H₂₈N₄O₂S: 436.19; Found: 437.3 (M+1)⁺.

Example 126 Compound 200

ESMS calcd. for C₂₂H₂₂N₄O₂S: 406.15; Found: 407.2 (M+1)⁺.

Example 127 Compound 201

ESMS calcd. for C₂₃H₂₄N₄O₃S: 436.16; Found: 437.3 (M+1)⁺.

Example 128 Compound 202

ESMS calcd. for C₂₂H₂₃N₄O₂S: 406.1; Found: 407.0 (M+H)⁺.

Example 129 Compound 204

ESMS calcd. for C₂₄H₂₈N₄O₃S: 452.19; Found: 453.2 (M+1)⁺.

Example 130 Compound 205

ESMS calcd. for C₂₃H₂₄N₄O₃S: 436.16; Found: 437.1 (M+1)⁺.

Example 131 Compound 206

ESMS calcd. for C₂₁H₂₃N₄O₂S: 394.1; Found: 395.1 (M+1)⁺.

Example 132 Compound 207

ESMS calcd. for C₂₀H₂₁N₄O₂S: 380.1; Found: 381.1 (M+1)⁺.

Example 133 Compound 208

ESMS calcd. for C₂₃H₂₆N₄O₃S: 438.17; Found: 439.1 (M+1)⁺.

Example 134 Compound 209

ESMS calcd. for C₂₂H₂₄N₄O₂S: 408.1; Found: 409.1 (M+1)⁺.

Example 135 Compound 210

ESMS calcd. for C₂₄H₂₃N₄O₂S: 430.1; Found: 431.1 (M+1)⁺.

Example 136 Compound 211

ESMS calcd. for C₂₁H₂₂N₄O₃S: 410.14; Found: 411.1 (M+1)⁺.

Example 137 Compound 212

ESMS calcd. for C₂₃H₂₆N₄O₃S: 438.17; Found: 439.1 (M+1)⁺.

Example 138 Compound 213

ESMS calcd. for C₂₀H₂₁N₄O₂S: 380.1; Found: 381.1 (M+1)⁺.

Example 139 Compound 214

ESMS calcd. for C₁₉H₁₉N₄O₂S: 366.1; Found: 367.1 (M+1)⁺.

Example 140 Compound 215

ESMS calcd. for C₂₀H₁₉N₃O₄S: 397.1; Found: 398.1 (M+1)⁺.

Example 141 Compound 216

¹H NMR (DMSO-d₆): δ (ppm) 9.56 (s, 1H), 9.40 (s, 1H), 8.03 (d, J=2.4 Hz,1H), 7.58 (d, J=8.4 Hz, 1H), 7.54 (d, J=2.1 Hz, 1H), 7.11 (dd, J=8.4,2.1 Hz, 1H), 6.97 (d, J=2.4 Hz, 1H), 6.89 (s, 1H), 6.17 (s, 1H), 2.23(q, J=7.2 Hz, 2H), 0.93 (t, J=7.2 Hz, 3H);

ESMS calcd. for C₁₈H₁₅N₃O₃S: 353.08; Found: 354.0 (M+1)⁺.

Example 142 Compound 217

¹H NMR (DMSO-d₆): δ (ppm) 9.59 (s, 1H), 9.43 (s, 1H), 7.67 (d, J=8.7 Hz,1H), 7.54 (d, J=2.1 Hz, 1H), 7.20 (dd, J=8.4, 2.1 Hz, 1H), 6.96 (s, 1H),6.18 (s, 1H), 2.60 (s, 3H), 2.34 (q, J=7.2 Hz, 2H), 0.98 (t, J=7.2 Hz,3H);

ESMS calcd. for C₁₈H₁₆N₄O₃S: 368.09; Found: 369.0 (M+1)⁺.

Example 143 Compound 218

ESMS calcd. for C₂₁H₂₃N₄O₂S: 394.1; Found: 395.1 (M+1)⁺.

Example 144 Compound 219

ESMS calcd. for C₂₁H₂₁N₄O₂S: 392.1; Found: 393.1 (M+1)⁺.

Example 145 Compound 220

ESMS calcd. for C₂₀H₂₁N₄O₃: 364.1; Found: 365.1 (M+1)⁺.

Example 146 Compound 221

ESMS calcd. for C₂₀H₂₁N₄O₂S: 379.1; Found: 381.1 (M+1)⁺.

Example 147 Compound 222

ESMS calcd. for C₂₁H₂₃N₄O₂S: 394.1; Found: 395.1(M+1)⁺.

Example 148 Compound 224

ESMS calcd. for C₁₉H₂₁N₄O₂S: 368.1; Found: 369.1 (M+1)⁺.

Example 149 Compound 225

ESMS calcd. for C₁₉H₁₉N₄O₂S: 366.1; Found: 367.1(M+1)⁺.

Example 150 Compound 226

ESMS calcd. for C₂₀H₂₁N₄O₃: 364.1; Found: 365.1 (M+1)⁺.

Example 151 Compound 227

ESMS calcd. for C₂₁H₂₂N₄O₂S: 394.15; Found: 395.1 (M+1)⁺.

Example 152 Compound 228

ESMS calcd. for C₂₂H₂₄N₄O₂S: 408.16; Found: 409.1 (M+1)⁺.

Example 153 Compound 229

ESMS calcd. for C₂₀H₁₈F₃N₅O₂S: 449.11; Found: 450.1 (M+1)⁺.

Example 154 Compound 230

ESMS calcd. for C₁₉H₁₉N₅O₂S: 381.13; Found: 382.1 (M+1)⁺.

Example 155 Compound 231

ESMS calcd. for C₁₉H₁₉N₅O₂S: 381.13; Found: 382.1 (M+1)⁺.

Example 156 Compound 232

ESMS calcd. for C₂₂H₂₄N₄O₃S: 392.18; Found: 393.1 (M+1)⁺.

Example 157 Compound 233

ESMS calcd. for C18H17N3O4S: 371.09; Found: 372.1 (M+1)+.

Example 158 Compound 234

ESMS calcd. for C20H21N3O2S: 367.14; Found: 368.1 (M+1)+.

Example 159 Compound 235

ESMS calcd. for C₁₉H₁₉N₅O₂S: 381.13; Found: 382.1 (M+1)⁺.

Example 160 Compound 239

ESMS clcd for C₁₉H₂₁N₄O₂S: 368.1; Found: 3.69.1 (M+H)⁺.

Example 161 Compound 240

ESMS clcd for C₁₈H₁₆N₄O₃S: 368.09.10; Found: 369.1 (M+H)⁺.

Example 162 Compound 241

ESMS clcd for C₁₇H₁₅N₅O₃S: 369.09; Found: 370.1 (M+H)⁺.

Example 163 Compound 242

ESMS clcd for C₁₉H₁₈N₄O₃S: 382.11; Found: 383.1 (M+H)⁺.

Example 164 Compound 243

ESMS clcd for C₂₂H₂₆N₄O₃S: 426.17; Found: 427.1 (M+H)⁺.

Example 165 Compound 244

ESMS clcd for C₁₈H₁₆N₄O₄S: 384.09; Found: 385.1 (M+H)⁺

Example 166 Compound 245

ESMS clcd for C₁₈H₁₆N₄O₃S₂: 400.07; Found: 401.1 (M+H)⁺

Example 167 Compound 245

ESMS clcd for C₁₇H₁₄N₄O₃S₂: 386.05; Found: 387.0 (M+H)⁺.

Example 168 Inhibition of HUVEC Cell Migration

To examine if the compounds of the invention affect endothelial cellfunction, an in vitro human umbilical vein endothelial cell (HUVEC)migration assay was performed in the presence of Compound 226. HUVECcells (ATCC, VA) (passage number 4) were cultured in EGM2 medium(Cambrex, Mass.) on 12-well plates and performed time-lapse imaging withthe live cell imaging system on an inverted microscope supplied with6-7% CO₂. The temperature was kept at 37° C. Images were taken every 30minutes using the 2× objective for up to 106 hr (results in FIGS. 1, 2and 3), or, every 60 seconds using the 20× objective for 30 min (forFIG. 4). Confluent HUVEC cultures were scraped similarly to make a blankarea, followed by culturing in HUVEC medium for 15 hr without treatment.The migration areas, which were imaged as time-lapse sequences for eachwell, were used as a basis to standardize/correct migration rates. Then,migration of cells under different treatments was imaged at the sametime to generate time-lapse image sequences for each well. Time-lapsemovies were further analyzed by measuring areas that were covered bymigrating cells. FIG. 1 shows cell migration during compound treatmentin different time points (0, 24, 48, 72 and 106 hrs). The red linesindicate the front lines of migrating cells. DMSO (1:100) treated cellsmigrated rapidly and covered the entire blank (wounded) area at 106 hr.However, compared to DMSO, Compound 226 (100 nM and 1 μM) completelyblocked migration of HUVEC cells to the blank area. The quantitativeanalysis of FIG. 1 is shown in FIG. 2. This demonstrates that coveredareas were similar between Compound 226, 100 nM and 1 μM treatment,indicating that the IC50 of the inhibition should be below 100 nM. As areference, a separate experiment was performed and showed that the IC50of Compound 226 for HUVEC killing was around 800 nM. Images with largermagnification (FIG. 3) showed that no significant cell death was seen at24 hr, suggesting that the observed migration inhibition was due to thelimited motility of HUVEC cells and not due to cell death. Duringexperiments, HUVEC cells were activated by the presence of VEGF(Cambrex, Mass.) and basic FGF (Cambrex, Mass.). Compound 226 possessespotent inhibitory effect on the migration of activated HUVEC cell invitro induced by VEGF and basic FGF.

In addition to the analysis of HUVEC cell migration, HUVEC behavior wasalso tracked during above treatments. We found HUVEC cells began toshrink after 24 hr treatment with 100 nM and 1 μM Compound 226. Thegreen arrows in FIG. 2 show that at 48 hr HUVEC cells retracted due tothe shrinking of the entire population. However, despite of cellshrinkage, the majority of cells were alive at 48 hr even under 1 μMCompound 226 treatment (see FIG. 3). Careful examination under largermagnification of microscopy (FIG. 4) reveals that HUVEC cells treatedwith Compound 226 at 100 nM or above appeared to contact to each othertightly. Cell-cell contact lines disappeared in 100 nM Compound 226treated population in both magnifications in FIG. 4. In time-lapsevideos captured with larger magnification objective (20×), significantlyreduced movement of HUVEC cells was observed when treated with 100 nMCompound 226, which was distinct from that of DMSO treated cells thatmoved in rapid speed. These changes of HUVEC cell behavior andmorphology suggested that Compound 226 may affect HUVEC cell-celljunction (see Example 169).

Example 169 Compound 226 Enhanced VE-Cadherin Junctions of HUVEC Cells

An immunofluorescence study was performed by using anti-VE-cadherinantibodies (1:1 mixed, obtained from Amersham Biosciences, NJ, and SantaCruz Biotechnology, CA) to examine VE-cadherin junctions between HUVECcells. HUVEC cells were treated with DMSO or Compound 226 (10, 100 and1000 nM) for 24 hrs and fixed for immunostaining. DMSO concentration was1:100 for all treatments. To boost the immunofluorescence signal, cellswere stained with a mixture of 2 polyclonal anti-human VE-cadherin Absfollowed by staining with a mixture of fluorescent secondary antibodies.FIG. 5 shows that VE-cadherin was stained strongly at the cell-celljunctions (red arrows in DMSO), but not the non-contacted regions ofcells (green arrows), in the DMSO control. Non-DMSO treated cells gave asimilar result to those with DMSO treatment (data not shown).Surprisingly, with 10 nM Compound 226 treatment, VE-cadherin stainingwas extremely strong in cell-cell junction regions, but not thenon-contacted regions (red arrow in Compound 226 10 nM) compared to thatin DMSO treated cultures. Increasing the Compound 226 concentration to100 nM seemed to further increase the VE-cadherin staining areas (redarrows in Compound 226 100 nM). Aggregations of VE-cadherin moleculesappeared in wells treated with higher concentration (1 μM). Theseresults strongly suggest that Compound 226 enhances the assembly ofcell-cell junctions of activated human endothelial cells, likely throughinduction of the accumulation of VE-cadherin molecules at the junctions.This effect could result in limited motility of the cells and reducingpermeability of the endothelium, thus contributing to the cell migrationinhibition and the potential anti-angiogenesis effect of Compound 226.

Example 170 Necrosis in a Nude Mouse Tumor Model

The mouse mammary carcinoma cell line, EMT6 (ATCC #CRL-2755), isobtained from the American Type Culture Collection (ATCC; Manassas, Va.,USA). The cell line is cultured in growth media prepared from 50%Dulbecco's Modified Eagle Medium (high glucose), 50% RPMI Media 1640,10% fetal bovine serum (FBS), 1% 100× L-glutamine, 1% 100×Penicillin-Streptomycin, 1% 100× sodium pyruvate and 1% 100× MEMnon-essential amino acids. FBS is obtained from ATCC and all otherreagents are obtained from Invitrogen Corp. (Carlsbad, Calif., USA).Approximately 4-5×10(6) cells that have been cryopreserved in liquidnitrogen are rapidly thawed at 37° C. and transferred to a 175 cm²tissue culture flask containing 50 ml of growth media and then incubatedat 37° C. in a 5% CO₂ incubator. The growth media is replaced every 2-3days until the flask became 90% confluent, typically in 5-7 days. Topassage and expand the cell line, a 90% confluent flask is washed with10 ml of room temperature phosphate buffered saline (PBS) and the cellsare disassociated by adding 5 ml 1× Trypsin-EDTA (Invitrogen) andincubating at 37° C. until the cells detach from the surface of theflask. To inactivate the trypsin, 5 ml of growth media is added and thenthe contents of the flask are centrifuged to pellet the cells. Thesupernatant is aspirated and the cell pellet is resuspended in 10 ml ofgrowth media and the cell number determined using a hemocytometer.Approximately 1-3×10(6) cells per flask are seeded into 175 cm² flaskscontaining 50 ml of growth media and incubated at 37° C. in a 5% CO₂incubator. When the flasks reach 90% confluence, the above passagingprocess is repeated until sufficient cells have been obtained forimplantation into mice.

Seven to eight week old, female Crl:CD-1-nuBR (nude) mice are obtainedfrom Charles River Laboratories (Wilmington, Mass., USA). Animals arehoused 4-5/cage in micro-isolators, with a 12 hr/12 hr light/dark cycle,acclimated for at least 1 week prior to use and fed normal laboratorychow ad libitum. Studies are conducted on animals between 8 and 10 weeksof age at implantation. To implant EMT6 tumor cells into nude mice, thecells are trypsinized as above, washed in PBS and resuspended at aconcentration of 10×10(6) cells/ml in PBS. Using a 27 gauge needle and 1cc syringe, 0.1 ml of the cell suspension is injected subcutaneouslyinto the flank of each nude mouse.

Tumors are then permitted to develop in vivo until the majority reached75-125 mm³ in tumor volume, which typically requires 1 week followingimplantation. Animals with oblong, very small or large tumors arediscarded, and only animals carrying tumors that display consistentgrowth rates are selected for studies. Tumor volumes (V) are calculatedby caliper measurement of the width (W), length (L) and thickness (T) oftumors using the following formula: V=0.5236×(L×W×T). Animals arerandomized into treatment groups so that each group had median tumorvolumes of ˜100 mm³ at the start of dosing.

To formulate a compound of the invention in DRD, a stock solution of thetest article is prepared by dissolving an appropriate amount of thecompound in dimethyl sulfoxide (DMSO) by sonication in an ultrasonicwater bath. A solution of 20% Cremophore RH40 (polyoxyl 40 hydrogenatedcastor oil; BASF Corp., Aktiengesellschaft, Ludwigshafen, Germany) in 5%dextrose in water (Abbott Laboratories, North Chicago, Ill., USA) isalso prepared by first heating 100% Cremophore RH40 at 50-60° C. untilliquefied and clear, diluting 1:5 with 100% D5W, reheating again untilclear and then mixing well. This solution is stored at room temperaturefor up to 3 months prior to use. To prepare a DRD formulation fordosing, the DMSO stock solution is diluted 1:10 with 20% CremophoreRH40. The final DRD formulation for dosing contains 10% DMSO, 18%Cremophore RH40, 3.6% dextrose, 68.4% water and the appropriate amountof test article.

Tumor-bearing animals are given a single intravenous (i.v.) bolusinjections of either DRD vehicle or a compound of the inventionformulated in DRD, both at 10 mL per kg body weight. Then, 4-24 hr afterdrug treatment, tumors are excised, cut in half and fixed overnight in10% neutral-buffered formalin. Each tumor is embedded in paraffin withthe cut surfaces placed downwards in the block, and rough cut until acomplete section is obtained. From each tumor, 5 μM serial sections areprepared and stained with hematoxylin and eosin. Slides are evaluatedmanually using light microscopy with a 10×10 square gridded reticle. Thepercentage of necrosis in a tumor is quantified at 200× magnification byscoring the total number of grid squares containing necrosis and thetotal number of grid squares containing viable tumor cells.

It is expected that compounds of the invention will result in anincrease in necrotic tissue in the center of EMT6 tumors relative to thebaseline necrosis observed in vehicle treated tumors. As would beexpected for a vascular targeting mechanism of action, rapid onset ofnecrosis is consistent with there being a loss of blood flow to tumorsresulting in hypoxia and tumor cell death.

Example 171 Vascular Disrupting Activities in a Nude Mouse Tumor Model

The mouse mammary carcinoma cell line, EMT6 (ATCC #CRL-2755), isobtained from the American Type Culture Collection (ATCC; Manassas, Va.,USA). The cell line is cultured in growth media prepared from 50%Dulbecco's Modified Eagle Medium (high glucose), 50% RPMI Media 1640,10% fetal bovine serum (FBS), 1% 100× L-glutamine, 1% 100×Penicillin-Streptomycin, 1% 100× sodium pyruvate and 1% 100× MEMnon-essential amino acids. FBS is obtained from ATCC and all otherreagents are obtained from Invitrogen Corp. (Carlsbad, Calif., USA).Approximately 4-5×10⁶ cells that have been cryopreserved in liquidnitrogen are rapidly thawed at 37° C. and transferred to a 175 cm²tissue culture flask containing 50 mL of growth media and then incubatedat 37° C. in a 5% CO₂ incubator. The growth media is replaced every 2-3days until the flask became 90% confluent, typically in 5-7 days. Topassage and expand the cell line, a 90% confluent flask is washed with10 mL of room temperature phosphate buffered saline (PBS) and the cellsare disassociated by adding 5 mL 1× Trypsin-EDTA (Invitrogen) andincubating at 37° C. until the cells detach from the surface of theflask. To inactivate the trypsin, 5 mL of growth media is added and thenthe contents of the flask are centrifuged to pellet the cells. Thesupernatant is aspirated and the cell pellet is resuspended in 10 mL ofgrowth media and the cell number determined using a hemocytometer.Approximately 1-3×10⁶ cells per flask are seeded into 175 cm² flaskscontaining 50 mL of growth media and incubated at 37° C. in a 5% CO₂incubator. When the flasks reach 90% confluence, the above passagingprocess is repeated until sufficient cells have been obtained forimplantation into mice.

Seven to eight week old, female Crl:CD-1-nuBR (nude) mice are obtainedfrom Charles River Laboratories (Wilmington, Mass., USA). Animals arehoused 4-5/cage in micro-isolators, with a 12 hr/12 hr light/dark cycle,acclimated for at least 1 week prior to use and fed normal laboratorychow ad libitum. Studies are conducted on animals between 8 and 10 weeksof age at implantation. To implant EMT6 tumor cells into nude mice, thecells are trypsinized as above, washed in PBS and resuspended at aconcentration of 10×10⁶ cells/mL in PBS. Using a 27 gauge needle and 1cc syringe, 0.1 mL of the cell suspension is injected subcutaneouslyinto the flank of each nude mouse.

For the Evans Blue dye assay, tumors are permitted to develop in vivountil the majority reach 40-90 mm³ in tumor volume (to minimize theextent of tumor necrosis), which typically require 4-6 days followingimplantation. Animals with visibly necrotic, oblong, very small or verylarge tumors are discarded and only animals carrying tumors that displayconsistent growth rates are selected for use. Tumor volumes (V) arecalculated by caliper measurement of the width (W), length (L) andthickness (T) of tumors using the following formula: V=0.5236×(L×W×T).Animals are randomized into treatment groups so that at the start ofdosing each group have median tumor volumes of ˜125 mm³ or ˜55 mm³ forthe Evans Blue dye assay.

To formulate compounds of the invention for dosing, the appropriateamount of compound is dissolved in 5% dextrose in water (D5W; AbbottLaboratories, North Chicago, Ill., USA). Vehicle-treated animals aredosed with D5W.

To conduct the Evans Blue dye assay, tumor-bearing animals are dosedwith vehicle or test article at 0 hr, and then i.v. injected with 100 μLof a 1% (w/v) Evan's Blue dye (Sigma #E-2129; St. Louis, Mo., USA)solution in 0.9%. NaCl at +1 hr. Tumors are excised at +4 hr, weighedand the tissue disassociated by incubation in 50 μL 1 N KOH at 60° C.for 16 hr. To extract the dye, 125 μL of a 0.6 N phosphoric acid and 325μL acetone are added, and the samples vigorously vortexed and thenmicrocentrifuged at 3000 RPM for 15 min to pellet cell debris. Theoptical absorbance of 200 μL of supernatant is then measured at 620 nMin a Triad spectrophotometer (Dynex Technologies, Chantilly, Va., USA).Background OD₆₂₀ values from similarly sized groups of vehicle or testarticle-treated animals that have not been injected with dye aresubtracted as background. OD₆₂₀ values are then normalized for tumorweight and dye uptake is calculated relative to vehicle-treated tumors.

To examine the vascular disrupting activity of a compound of theinvention, the Evans Blue dye assay is employed as a measurement oftumor blood volume (Graff et al., Eur J Cancer 36:1433-1440, 2000).Evans Blue dye makes a complex with serum albumin by electrostaticinteraction between the sulphonic acid group of the dye and the terminalcationic nitrogens of the lysine residues in albumin. The dye leaves thecirculation very slowly, principally by diffusion into extravasculartissues while still bound to albumin. Albumin-dye complex taken up bytumors is located in the extracellular space of non-necrotic tissue, andintracellular uptake and uptake in necrotic regions is negligible. Theamount of dye present in a tumor is a measurement of the tumor bloodvolume and microvessel permeability. Compounds of the invention areexpected to result in substantially decreased tumor dye uptake relativeto vehicle-treated animals. Such a decrease in dye penetration into thetumor is consistent with there being a loss of blood flow to tumors dueto blockage of tumor vasculature, consistent with a vascular disruptingmechanism of action.

All publications, patent applications, patents, and other documentscited herein are incorporated by reference in their entirety. In case ofconflict, the present specification, including definitions, willcontrol. In addition, the materials, methods, and examples areillustrative only and not intended to be limiting.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1. A method of treating, reducing or inhibiting a disease associatedwith angiogenesis in a subject in need thereof, comprising administeringto the subject an effective amount of a compound represented by thefollowing structural formula:

or a tautomer or pharmaceutically acceptable salt thereof, wherein: ringA is an aryl or a heteroaryl, wherein the aryl or the heteroaryl areoptionally further substituted with one or more substituents in additionto R₃; R₁ and R₃ are, independently, —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆,—NHR₂₆, —O(CH₂)_(m)OH, —O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH,—S(CH₂)_(m)SH, —S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇,—NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇,—SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁,—NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇, —SS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₇S(O)_(p)R₇, —OS (O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇,—OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇,—NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —OP(O)(OR₇)₂, or —SP(O)(OR₇)₂; R₅ isan optionally substituted heteroaryl or an optionally substituted 8 to14 membered aryl; R₇ and R₈, for each occurrence, are, independently,—H, an optionally substituted alkyl, an optionally substituted alkenyl,an optionally substituted alkynyl, an optionally substituted cycloalkyl,an optionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, or an optionallysubstituted heteraralkyl; R₁₀ and R₁₁, for each occurrence, areindependently —H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; or R₁₀ and R₁₁, taken togetherwith the nitrogen to which they are attached, form an optionallysubstituted heterocyclyl or an optionally substituted heteroaryl; R₂₆ isa C1-C6 alkyl; p, for each occurrence, is, independently, 0, 1 or 2; andm, for each occurrence, is independently, 1,2, 3, or 4; provided thatring A is not a substituted [1,2,3]triazole; and provided that thecompound is not 3-(2,4-dihydroxy-phenyl)-4-(7-naphthalen-1-yl)-5-mercapto-triazole; wherein the disease isselected from ocular neovascular disease; age-related maculardegeneration; diabetic retinopathy; retinopathy of prematurity; cornealgraft rejection; neovascular glaucoma; retrolental fibroplasias;epidemic keratoconjunctivitis; Vitamin A deficiency; contact lensoverwear; atopic keratitis; superior limbic keratitis; pterygiumkeratitis sicca; sjogrens; acne rosacea; warts; eczema; phylectenulosis;syphilis; Mycobacteria infections; lipid degeneration; chemical burns;bacterial ulcers; fungal ulcers; Herpes simplex infections; Herpeszoster infections; protozoan infections; Kaposi's sarcoma; Mooren'sulcer; Terrien's marginal degeneration; marginal keratolysis; rheumatoidarthritis; systemic lupus; polyarteritis; trauma; Wegener's sarcoidosis;scleritis; Stevens-Johnson disease; pemphigoid; radial keratotomy;corneal graph rejection; diabetic retinopathy; macular degeneration;sickle cell anemia; sarcoid; syphilis; pseudoxanthoma elasticum; Paget'sdisease; vein occlusion; artery occlusion; carotid obstructive disease;chronic uveitis vitritis; mycobacterial infections; Lyme's disease;systemic lupus erythematosis; retinopathy of prematurity; Eales'disease; Behcet's disease; infections causing a retinitis orchoroiditis; presumed ocular histoplasmosis; Best's disease; myopia;optic pits; Stargardt's disease; pars planitis; chronic retinaldetachment, hyperviscosity syndromes; toxoplasmosis; trauma andpost-laser complications; diseases associated with rubeosis(neovasculariation of the angle); diseases caused by the abnormalproliferation of fibrovascular or fibrous tissue including all forms ofproliferative vitreoretinopathy; rheumatoid arthritis; osteoarthritis:ulcerative colitis; Crohn's disease; Bartonellosis; artherosclerosis;Osler-Weber-Rendu-disease; hereditary hemorrhagic telangiectasia;pulmonary hemangiomatosis; pre-eclampsia; endometriosis; fibrosis of theliver and of the kidney; developmental abnormalities (organogenesis);skin disclolorations; wound healing; hypertrophic scars; woundgranulation; vascular adhesions; cat scratch disease (Rochele ninaliaquintosa); ulcers (Helicobacter pylori); keratoconjunctivitis;gingivitis; periodontal disease; epulis; hepatitis; tonsilitis; obesity;rhinitis; laryngitis; tracheitis; bronchitis; bronchiolitis; pneumonia;interstitial pulmonary fibrosis; pulmonary edema; neurodermitis;thyroiditis; thyroid enlargement; endometriosis; glomerulonephritis;gastritis; inflammatory bone and cartilage destruction; thromboembolicdisease; and Buerger's disease.
 2. The method of claim 1, wherein R₅ isrepresented by the following formula:

wherein: R₉, for each occurrence, is independently a substituentselected from the group consisting of an optionally substituted alkyl,an optionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl,hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, aheteroalkyl, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂; or two R₉ groups taken together with the carbon atoms towhich they are attached form a fused ring; and m is zero or an integerfrom 1 to
 7. 3. The method of claim 1, wherein R₅ is represented by thefollowing structural formula:

wherein: R₃₃ is a halo, lower alkyl, a lower alkoxy, a lower haloalkyl,a lower haloalkoxy, and lower alkyl sulfanyl; R₃₄ is H, a lower alkyl,or a lower alkylcarbonyl; and Ring B and Ring C are optionallysubstituted with one or more substituents.
 4. The method of claim 1,wherein R₅ is an optionally substituted indolyl, an optionallysubstituted benzoimidazolyl, an optionally substituted indazolyl, anoptionally substituted 3H-indazolyl, an optionally substitutedindolizinyl, an optionally substituted quinolinyl, an optionallysubstituted isoquinolinyl, an optionally substituted benzoxazolyl, anoptionally substituted benzo[1,3]dioxolyl, an optionally substitutedbenzofuryl, an optionally substituted benzothiazolyl, an optionallysubstituted benzo[d]isoxazolyl, an optionally substitutedbenzo[d]isothiazolyl, an optionally substitutedthiazolo[4,5-c]pyridinyl, an optionally substitutedthiazolo[5,4-c]pyridinyl, an optionally substitutedthiazolo[4,5-b]pyridinyl, an optionally substitutedthiazolo[5,4-b]pyridinyl, an optionally substitutedoxazolo[4,5-c]pyridinyl, an optionally substitutedoxazolo[5,4-c]pyridinyl, an optionally substitutedoxazolo[4,5-b]pyridinyl, an optionally substitutedoxazolo[5,4-b]pyridinyl,an optionally substituted imidazopyridinyl, anoptionally substituted benzothiadiazolyl, benzoxadiazolyl, an optionallysubstituted benzotriazolyl, an optionally substituted tetrahydroindolyl,an optionally substituted azaindolyl, an optionally substitutedquinazolinyl, an optionally substituted purinyl, an optionallysubstituted imidazo[4,5-a]pyridinyl, an optionally substitutedimidazo[1,2-a]pyridinyl, an optionally substituted3H-imidazo[4,5-b]pyridinyl, an optionally substituted1H-imidazo[4,5-b]pyridinyl, an optionally substituted1H-imidazo[4,5-c]pyridinyl, an optionally substituted3H-imidazo[4,5-c]pyridinyl, an optionally substituted pyridopyrdazinyl,and optionally substituted pyridopyrimidinyl, an optionally substitutedpyrrolo[2,3]pyrimidyl, an optionally substituted pyrazolo[3,4]pyrimidylan optionally substituted cyclopentaimidazolyl, an optionallysubstituted cyclopentatriazolyl, an optionally substitutedpyrrolopyrazolyl, an optionally substituted pyrroloimidazolyl, anoptionally substituted pyrrolotriazolyl, or an optionally substitutedbenzo(b)thienyl.
 5. The method of claim 1, wherein the compound isrepresented by the following structural formula:

or a tautomer or pharmaceutically acceptable salt thereof, wherein: R₆,for each occurrence, is independently an optionally substituted alkyl,an optionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteroaralkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy,—NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇, —C(S)SR₇,—C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂; and n is zero of an integer from 1 to
 4. 6. A method oftreating, reducing or inhibiting a disease associated with angiogenesisin a subject in need thereof, comprising administering to the subject aneffective amount of a compound represented by the following structuralformula:

or a tautomer or pharmaceutically acceptable salt thereof, wherein R₂ isa substituted phenyl, wherein the phenyl group is substituted with: i)one substituent selected from nitro, cyano, a haloalkoxy, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, hydroxylalkyl, alkoxyalkyl,guanadino, —NR₁₀R₁₁, —O—R₂₀, —C(O)R₇, —C(O)OR₂₀, —OC(O)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —S(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂; or ii) two to five substituents selected from the groupconsisting of an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, —F, —Br, —I, cyano,nitro, guanadino, a haloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇, —C(O)R₇,—C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, —S(O)_(p)NR₁₀R₁₁,—OP(O)(OR₇)₂, or —SP(O)(OR₇)₂, —S(O)_(p)OR₇; wherein the disease isselected from ocular neovascular disease; age-related maculardegeneration; diabetic retinopathy, retinopathy of prematurity; cornealgraft rejection; neovascular glaucoma; retrolental fibroplasias;epidemic keratoconjunctivitis; Vitamin A deficiency; contact lensoverwear; atopic keratitis; superior limbic keratitis; pterygiumkeratitis sicca; sjogrens; acne rosacea; warts; eczema; phylectenulosis;syphilis; Mycobacteria infections; lipid degeneration; chemical burns;bacterial ulcers; fungal ulcers; Herpes simplex infections; Herpeszoster infections; protozoan infections; Kaposi's sarcoma; Mooren'sulcer; Terrien's marginal degeneration; mariginal keratolysis;rheumatoid arthritis; systemic lupus; polyarteritis; trauma; Wegener'ssarcoidosis; scleritis; Stevens-Johnson disease; pemphigoid; radialkeratotomy; corneal graph rejection; diabetic retinopathy; maculardegeneration; sickle cell anemia; sarcoid; syphilis; pseudoxanthomaelasticum; Paget's disease; vein occlusion; artery occlusion; carotidobstructive disease; chronic uveitis/vitritis; mycobacterial infections;Lyme's disease; systemic lupus erythematosis; retinopathy ofprematurity; Eales' disease; Behcet's disease; infections causing aretinitis or choroiditis; presumed ocular histoplasmosis; Best'sdisease; myopia; optic pits; Stargardt's disease; pars planitis; chronicretinal detachment; hyperviscosity syndromes; toxoplasmosis; trauma andpost-laser complications; diseases associated with rubeosis(neovasculariation of the angle); diseases caused by the abnormalproliferation of fibrovascular or fibrous tissue including all forms ofproliferative vitreoretinopathy; rheumatoid arthritis; osteoarthritis;ulcerative colitis; Crohn's disease; Bartonellosis; atherosclerosis;Osler-Weber-Rendu disease; hereditary hemorrhagic telangiectasia;pulmonary hemangiomatosis; pre-eclampsia; endometriosis; fibrosis of theliver and of the kidney; developmental abnormalities (organogenesis);skin disclolorations; wound healing; hypertrophic scars; woundgranulation; vascular adhesions; cat scratch disease (Rochele ninaliaquintosa); ulcers (Helicobacter- pylori); keratoconjunctivitis;gingivitis; periodontal disease; epulis; hepatitis; tonsillitis;obesity; rhinitis; laryngitis; tracheitis; bronchitis; bronchiolitis;pneumonia; interstitial pumnonary fibrosis; pulmonary edema;⁻neurodermitis; thyroiditis; thyroid enlargement; endometriosis;glomerulonephritis; gastritis; inflammatory bone and cartilagedestruction; thromboembolic disease; and Buerger's disease.
 7. Themethod of claim 5, wherein the compound is represented by the followingstructural formula:

or a tautomer or pharmaceutically acceptable salt thereof, wherein: R₂₅is an optionally substituted alkyl, an optionally substituted alkenyl,an optionally substituted alkynyl, an optionally substituted cycloalkyl,an optionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, aheteroalkyl, alkoxy, haloalkoxy, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇,—C(S)R₇, —C(O)SR₇, —C(S)SR₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇,—OC(NR₈)OR₇, —SC(O)R₇, —SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇,—SC(S)OR₇, —OC(O)NR₁₀R₁₁, —OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇,—NR₇C(NR₈)OR₇, —NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁,—SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇,—S(O)_(p)NR₁₀R₁₁, —SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁,—OP(O)(OR₇)₂, or —SP(O)(OR₇)₂; k is 1, 2, 3, or 4; and r is zero or aninteger from 1 to
 3. 8. The method of claim 7 wherein R₁, R₃ and R₂₅ areeach independently —OH, —SH, —NHR₇, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—SS(O)_(p)R₇, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —OP(O)(OR₇)₂ or —SP(O)(OR₇)₂. 9.The method of claim 7, wherein R₁ and R₃ are each, independently, —OH,—SH, or —NHR₇.
 10. The method of claim 9, wherein the compound isrepresented by the following structural formula:

or a tautomer or pharmaceutically acceptable salt thereof; wherein R₆ isan optionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, cyano, halo, nitro, an optionallysubstituted cycloalkyl, haloalkyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteroaralkyl, —OR₇, —SR₇, —NR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇,—NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇,—SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁,—NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇, —SS(O)_(p)R₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —C(O)NR₁₀R₁₁,—C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,or —S(O)_(p)R₇.
 11. The method of claim 10, wherein: R₁ is —SH or —OH;R₃ and R₂₅ are —OH; R₆ is a lower alkyl, C3-C6 cycloalkyl, lower alkoxy,a lower alkyl sulfanyl, or —NR₁₀R₁₁; and R₉, for each occurrence, isindependently selected from the group consisting of —OH, —SH, halo, alower haloalkyl, cyano, a lower alkyl, a lower alkoxy, and a lower alkylsulfanyl.
 12. The method of claim 10, wherein R₆ is a C1-C6 alkyl, aC1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkylsulfanyl or a C3-C6 cycloalkyl, and R₁ and R₃ are each, independently,—OH, —SH, or —NHR₇.
 13. The method of claim 12, wherein: R₁ is —SH or—OH; R₃ and R₂₅ are —OH; R₆ is a lower alkyl, C3-C6 cycloalkyl, loweralkoxy, a lower alkyl sulfanyl, or —NR₁₀R₁₁.
 14. The method of claim 1,wherein the compound is selected form the group consisting of:3-(2-Hydroxyphenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-[4-(2-methoxyethoxy)-naphthalen-1-yl]-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2-methyl-4-bromophenyl)-5-mercapto-triazole;3-(3,4-Dihydroxyphenyl)-4-(6-methoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(3,4-Dihydroxyphenyl)-4-(6-ethoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(3,4-Dihydroxyphenyl)-4-(6-propoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(5-methoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(3,4-Dihydroxyphenyl)-4-(6-isopropoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2,6-diethylphenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2-methyl-6-ethylphenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2,6-diisopropylphenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(1-ethyl-indol-4-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(3-methylphenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(4-methylphenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2-Chlorophenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(3-Chlorophenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(4-Chlorophenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2-methoxyphenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(3-methoxyphenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(3-fluorophenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2-ethylphenyl)-5-mercapto-triazole;3-(2-Hydroxy-4-fluorophenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2-Hydroxy-4-aminophenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2-methyl-4-butyl-phenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2,4-dimethyl-phenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2,6-dimethyl-phenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2,6-dimethyl-phenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(4-fluorophenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2-methylsulfanylphenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(naphthalene-2-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2,3-dimethylphenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2-methyl-4-fluorophenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(acenaphthalen-5-yl)-5-mercapto-triazole;3-(2-Hydroxy-4-methoxy-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2,3-dichlorophenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(5-methoxynaphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(pyren-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(quinolin-5-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(1,2,3,4-tetrahydronaphthalen-5-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(anthracen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(biphenyl-2-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-6-methyl-phenyl)-4-(naphthalene-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(4-pentyloxyphenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(4-octyloxyphenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(4-chloronaphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(7-carboxymethoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2-methyl-quinolin-4-yl)-5-mercapto-triazole;3-(3-Hydroxypyridin-4-yl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2-Hydroxy-4-acetylamino-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(1,2,3,4-tetrahydronaphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(3,5-dimethoxyphenyl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(2,3-dimethyl-1H-indol-4-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-3-propyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(4,6-Dihydroxy-1-ethyl-pyridin-3-yl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(4,6-Dihydroxy-1-methyl-pyridin-3-yl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(3,5-di-tert-butylphenyl)-5-mercapto-triazole;3-(2,6-Dihydroxy5-fluoro-pyridin-3-yl)4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-methyl-phenyl)-4-(naphthalene-1-yl)-5-mercapto-triazole;3-[2,4-Dihydroxy-phenyl]-4-(3-benzoylphenyl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(4-carboxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-[4-(N,N-dimethylcarbamoyl)-naphthalen-1-yl]-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(4-propoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(4-isopropoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(5-isopropoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(isoquinolin-5-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(5-propoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2-Hydroxy-4-methanesulfonamino-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-3,6-dimethyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-[7-(2-methoxyethoxy)-naphthalen-1-yl]-5-mercapto-triazole;3-(2,4-Dihydroxy-5-hexyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(4-methoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(6-methoxy-naphthalin-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-3-Chloro-5-ethyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(2,3-dimethyl-4-methoxy-phenyl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(7-isopropoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(7-ethoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(7-propoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2-Hydroxy-4-methoxymethyoxy-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-[2-Hydroxy-4-(2-hydroxy-ethoxy)-phenyl]-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(7-methoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(5-methoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(4-hydroxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(1-isopropyl-indol-4-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-tert-butyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-propyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-3-methyl-5-ethyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-isobutyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(2,3-dimethoxy-phenyl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(2-methoxy-3-Chloro-phenyl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(indol-4-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-[1-(2-methoxyethoxy)-indol-4-yl]-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(naphthalen-1-yl)-5-hydroxy-triazole;3-(1-Oxo-3-hydroxy-pyridin-4-yl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,5-Dihydroxy-4-carboxy)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-indol-4-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-[1-(dimethyl-carbamoyl)-indol-4-yl]-5-mercapto-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-ethyl-benzoimidazol-4-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1,2,3-trimethyl-indol-5-yl)-5-mercapto-triazole;3-(2,5-Dihydroxy-4-hydroxymethyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2-Hydroxy-4-amino-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2-Hydroxy-4-acetylamino-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-3-Chloro-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(3-methoxy-phenyl)-5-hydroxy-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(naphthalen-1-yl)-5-hydroxy-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-indol-3-yl)-5-hydroxy-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-indol-4-yl)-5-amino-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(3-methoxy-phenyl)-5-amino-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(naphthalen-1-yl)-5-amino-triazole;3-(2-Hydroxy-5-ethyloxy-phenyl)-4-(naphthalen-1-yl)-5-hydroxy-triazole;3-(2-Hydroxy-5-isopropyl-phenyl)-4-(naphthalen-1-yl)-5-hydroxy-triazole;3-(2-Dihydroxy-phenyl)-4-(7-fluoro-naphthalen-1-yl)-5-hydroxy-triazole;3-(2,4-Dihydroxy-phenyl)-4-(2,3-difluorophenyl)-5-hydroxy-triazole;3-(2,4-Dihydroxy-phenyl)-4-[2-(1H-tetrazol-5-yl)-phenyl]-5-hydroxy-triazole;3-(2,4-Dihydroxy-phenyl)-4-(benzothiazol-4-yl)-5-hydroxy-triazole;3-(2,4-Dihydroxy-phenyl)-4-(9H-purin-6-yl)-5-hydroxy-triazole;3-(2,4-Dihydroxy-phenyl)-4-{4-[2-(moropholin-1-yl)-ethoxy]-phenyl}-5-hydroxy-triazole;3-(2,4-Dihydroxy-phenyl)-4-cyclopentyl-5-hydroxy-triazole;3-(2,4-Dihydroxy-phenyl)-4-phenyl-5-(sulfamoylamino)-triazole;3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(naphthalene-1-yl)-5-ureido-triazole;3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(2,3-difluorophenyl)-5-ureido-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-indol-4-yl)-5-ureido-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(quinolin-5-yl)-5-ureido-triazole;3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(naphthalene-1-yl)-5-carbamoyloxy-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(3-trifluoromethyl-phenyl)-5-carbamoyloxy-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-methyl-indol-4-yl)-5-carbamoyloxy-triazole;3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(8-methoxy-quinolin-5-yl)-5-carbamoyloxy-triazole;3-(2,4-Dihydroxy-5-isopropyl-phenyl)-4-(3-methyl-quinolin-5-yl)-5-carboxyamino-triazole;3-(2,4-Dihydroxy-phenyl)-4-(1-methyl-2-Chloro-indol-4-yl)-5-carbamoyloxy-triazole;3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-[3,5-di-(trifluoromethyl)-phenyl]-5-carbamoyloxy-triazole;3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(3-trifluoromethyl-phenyl)-5-(sulfamoylamino)-triazole;3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(naphthalene-1-yl)-5-(sulfamoylamino)-triazole;3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(1-isopropyl-benzoimidazol-4-yl)-5-(sulfamoylamino)-triazole;3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(3-isopropylphenyl)-5-(thiocarboxyamino)-triazole;3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(3-isopropyloxy-phenyl)-5-(sulfamoyloxy)-triazole;3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(naphthalene-1-yl)-5-(sulfamoyloxy)-triazole;3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(5-hydroxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(naphthalen-1-ylmethyl)-5-mercapto-triazole;3-(2-Hydroxy-4-methoxyphenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(biphenyl-3-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(2-methyl-5-hydroxymethyl-phenyl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(1-dimethylcarbamoyl-indol-4-yl)-5-mercapto-triazole;3-(2,4,5-Trihydroxy-phenyl)-4-(naphthalene-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(2,3-dimethyl-indol-5-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(3-t-butyl-4-methoxy-phenyl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-ethyl-1H-benzoimidazol-4-yl)-5-mercapto-triazole,HCl salt;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-triazole;and3-(2,4-Dihydroxy-5-cyclopropyl-phenyl)-4-(naphthalene-1-yl)-5-mercapto-triazoleor a tautomer or pharmaceutically acceptable salt thereof.
 15. A methodof treating or inhibiting a disease associated with angiogenesis in asubject in need thereof, comprising administering to the subject aneffective amount of a compound represented by the following structuralformula:

or a tautomer or pharmaceutically acceptable salt thereof, wherein: X₄₁is O, S, or NR₄₂; X₄₂ is CR₄₄ or N; Y₄₀ is N or CR₄₃; Y₄₁ is N or CR₄₅;Y₄₂, for each occurrence, is independently N, C or CR₄₆; Z is OH, SH, orNHR₇; R₄₁ is —H, —OH, —SH, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, an alkoxy orcycloalkoxy, a haloalkoxy, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇,—C(O)SR₇, —C(S)SR₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇,—C(NR₈)NIZ₁₀R₁₁, —C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇,—OC(NR₈)OR₇, —SC(O)R₇, —SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇,—SC(S)OR₇, —OC(O)NR₁₀R₁₁, —OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇,—NR₇C(NR₈)OR₇, —NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁,—SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇,—S(O)_(p)NR₁₀R₁₁, —SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁,—OP(O)(OR₇)₂, or —SP(O)(OR₇)₂; R₄₂ is —H, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl,hydroxyalkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl, —C(O)R₇,—(CH₂)_(m)C(O)OR₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —S(O)_(p)R₇,—S(O)_(p)OR₇, or —S(O)_(p)NR₁₀R₁₁; R₄₃ and R₄₄ are, independently, —H,—OH, an optionally substituted alkyl, an optionally substituted alkenyl,an optionally substituted alkynyl, an optionally substituted cycloalkyl,an optionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino,a haloalkyl, a heteroalkyl, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —S(O)_(p)NR₁₀R₁₁, or R₄₃ and R₄₄ taken together with thecarbon atoms to which they are attached form an optionally substitutedcycloalkenyl, an optionally substituted aryl, an optionally substitutedheterocyclyl, or an optionally substituted heteroaryl; R₄₅ is —H, —OH,—SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH, —O(CH₂)_(m)SH,—O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH, —S(CH₂)_(m)SH, —S(CH₂)_(m)NR₇H,—OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇,—NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇,—NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇,—OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇,—SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇,—OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇,—NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, or —NR₇C(NR₈)NR₁₀R₁₁; R₄₆, for each occurrence, isindependently, selected from the group consisting of H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR₁₀R₁₁,—OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇,—S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or—S(O)_(p)NR₁₀R₁₁; R₇ and R₈, for each occurrence, are, independently,—H, an optionally substituted alkyl, an optionally substituted alkenyl,an optionally substituted alkynyl, an optionally substituted cycloalkyl,an optionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, or an optionallysubstituted heteraralkyl; R₁₀ and R₁₁, for each occurrence, areindependently —H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; or R₁₀ and R₁₁, taken togetherwith the nitrogen to which they are attached, form an optionallysubstituted heterocyclyl or an optionally substituted heteroaryl; R₂₆,for each occurrence is, is independently, a lower alkyl; p, for eachoccurrence, is, independently, 1 or 2; and m, for each occurrence, isindependently, 1, 2, 3, or 4; wherein the disease is selected fromocular neovascular disease; age-related macular degeneration; diabeticretinopathy, retinopathy ofprematurity; corneal graft rejection;neovascular glaucoma; retrolental fibroplasias; epidemickeratoconjunctivitis; Vitamin A deficiency, contact lens overwear;atopic keratitis; superior limbic keratitis; pterygium keratitis sicca;sjogrens; acne rosacea; warts; eczema; phylectenulosis; syphilis;Mycobacteria infections; lipid degeneration; chemical burns; bacterialUlcers; fungal ulcers; Herpes simplex infections; Herpes zosterinfections; protozoan infections; Kaposi's sarcoma; Mooren's ulcer;Terrien's marginal degeneration; mariginal keratolysis; rheumatoidarthritis; systemic lupus; polyarteritis; trauma; Wegener's sarcoidosis;scleritis; Stevens-Johnson disease; pemphigoid; radial keratotomy;corneal graph rejection; diabetic retinopathy; macular degeneration;sickle cell anemia; sarcoid; syphilis; pseudoxanthoma elasticum; Paget'sdisease; vein occlusion; artery occlusion; carotid obstructive disease;chronic uveitis/vitritis; mycobacterial infections; Lyme's disease;systemic lupus erythematosis; retinopathy ofprematurity; Eales' disease;Behcet's disease; infections causing a retinitis or choroiditis;presumed ocular histoplasmosis; Best's disease; myopia; optic pits;Stargardt's disease; pars planitis; chronic retinal detachment;hyperviscosity syndromes; toxoplasmosis; trauma and post-lasercomplications; diseases associated with rubeosis (neovasculariation ofthe angle); diseases caused by the abnormal proliferation offibrovascular or fibrous tissue including all forms of proliferativevitreoretinopathy; rheumatoid arthritis; osteoarthritis ulcerativecolitis; Crohn's disease; Bartonellosis; atherosclerosis; Osler-Weber-Rendu disease; hereditary hernoniagictelangiectasia; pulmonaryheniangiomatosis; pre- eclampsia; endometriosis; fibrosis of the liverand of the kidney; developmental abnormalities, (organogenesis); skindisclolorations; wound healing; hypertrophic scars; wound granulation;vascular adhesions; cat scratch disease (Rochele ninalia quintosa);ulcers (Helicohacter pylori); keratoconjunctivitis; gingivitis;periodontal disease; epulis; hepatitis; tonsillitis; obesity; rhinitis;laryngitis; tracheitis; bronchitis; bronchiolitis; pneumonia;interstitial pulmonary fibrosis; pulmonary edema; neurodermitis;thyroiditis; thyroid enlargement; endometriosis; glomerulonephritis;gastritis; inflammatory bone and cartilage destruction; thromboembolicdisease; and Buerger's disease.
 16. The method of claim 15, wherein X₄₁is NR₄₂ and X₄₂ is CR₄₄.
 17. The method of claim 15, wherein X₄₁ isNR₄₂, and R₄₂ is selected from the group consisting of —H, methyl,ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, sec-butyl, tert-butyl,n-pentyl, n-hexyl, —C(O)OH, —(CH₂)_(m)C(O)OH, —CH₂OCH₃, —CH₂CH₂OCH₃, and—C(O)N(CH₃)₂.
 18. The method of claim 15, wherein R₄₃ and R₄₄ are,independently, selected from the group consisting of —H, methyl, ethyl,propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy, andcyclopropoxy; and Z is —OH or —SH.
 19. The method of claim 15, whereinthe compound is selected from the group consisting of:3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2-methyl-7-methoxy-benzofuran-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(benzofuran-5-yl)-5-mercapto-[1,2,4]triazole,and3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2-methyl-1,3-benzoxaz-5-yl)-5-mercapto-[1,2,4]triazole.20. The method of claim 15 wherein the compound is represented by thefollowing structural formula:

or a tautomer or pharmaceutically acceptable salt thereof, wherein Z₁ is—OH or —SH.
 21. The method of claim 20, wherein X₄₂ is CR₄₄, and R₄₃ andR₄₄ are, independently, selected from the group consisting of —H,methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy,and cyclopropoxy.
 22. The method of claim 20, wherein: X₄₅ is CR₅₄ or N;R₅₆ is selected from the group consisting of —H, methyl, ethyl,isopropyl, and cyclopropyl; R₅₂ is selected from the group consisting of—H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl,—(CH₂)₂OCH₃, —CH₂C(O)OH, and —C(O)N(CH₃)₂; R₅₃ and R₅₄ are each,independently, —H, methyl, ethyl, or isopropyl; or R₅₃ and R₅₄ takentogether with the carbon atoms to which they are attached form a phenyl,cyclohexenyl, or cyclooctenyl ring; and R₅₅ is selected from the groupconsisting of —H, —OH, —OCH₃, and —OCH₂CH₃.
 23. The method of claim 15,wherein the compound is selected from the group consisting of:3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-isopropyl-indol-4-yl)-5-hydroxy-[1,2,4]triazole;3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indazol-5-yl)-5-mercapto-[1,2,4]triazole;3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indazol-6-yl)-5-mercapto-[1,2,4]triazole;3-(2,4-dihydroxyphenyl)-4-(1-ethyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxyphenyl)-4-(1-isopropyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxyphenyl)-4-(indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxyphenyl)-4-(1-methoxyethyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxyphenyl)-4-(1-dimethylcarbamoyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethylphenyl)-4-(1-propyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,2,3-trimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-acetyl-2,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-propyl-2,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-methyl-tetrahydrocarbozol-7-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-methyl-cyclononan[a]indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-n-butyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-n-pentyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-n-hexyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1-(1-methylcyclopropyl)-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1,2,3-trimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazoledisodium salt,3-(2,4-dihydroxy-5-tert-butyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1-propyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-methyl-3-ethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-methyl-3-isopropyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-ethyl-carbozol-7-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-7-hydroxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-7-ethoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,2-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-methyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1H-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,2-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-ethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-propyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-ethyl-benzimidazol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-ethyl-benzimidazol-4-yl)-5-mercapto-[1,2,4]triazoleHCL salt,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2-methyl-3-ethyl-benzimidazol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-ethyl-2-methyl-benzimidazol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-2-trifluoromethyl-benzimidazol-5-yl)-5-mercapto-[1,2,4]triazole;and3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(N-methyl-indol-5-yl)-5-mercapto-[1,2,4]triazole;or tautomers or pharmaceutically acceptable salts thereof.
 24. A methodof blocking, occluding, or otherwise disrupting blood flow in a diseaseassociated with neovasculature, comprising contacting the neovasculaturewith an effective amount of a compound represented by the followingstructural formula:

or a tautomer or pharmaceutically acceptable salt thereof, wherein: ringA is an aryl or a heteroaryl, wherein the aryl or the heteroaryl areoptionally further substituted with one or more substituents in additionto R₃; R₁ and R₃ are, independently, —OH, —SH, —NR₇H, —OR₂₆, —SR₂₆,—NHR₂₆, —O(CH₂)_(m)OH, —O(CH₂)_(m)SH, —O(CH₂)_(m)NR₇H, —S(CH₂)_(m)OH,—S(CH₂)_(m)SH, —S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇,—NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇,—SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁,—NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇, —SS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇,—OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇,—NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —OP(O)(OR₇)₂, or —SP(O)(OR₇)₂; R₅ isan optionally substituted heteroaryl or an optionally substituted 8 to14 membered aryl; R₇ and R₈, for each occurrence, are, independently,—H, an optionally substituted alkyl, an optionally substituted alkenyl,an optionally substituted alkynyl, an optionally substituted cycloalkyl,an optionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, or an optionallysubstituted heteraralkyl; R₁₀ and R₁₁, for each occurrence, areindependently —H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; or R₁₀ and R₁₁, taken togetherwith the nitrogen to which they are attached, form an optionallysubstituted heterocyclyl or an optionally substituted heteroaryl; R₂₆ isa C1-C6 alkyl; p, for each occurrence, is, independently, 0, 1 or 2; andm, for each occurrence, is independently, 1, 2, 3, or 4; provided thatring A is not a substituted [1,2,3]triazole; and provided that thecompound is not3-(2,4-dihydroxy-phenyl)-4-(7-naphthalen-1-yl)-5-mercapto-triazole,wherein the neovasculature is in a subject in need of treatment toblock, occlude or otherwise disrupt blood flow in the neovasculature;wherein the disease is selected from infectious diseases; autoimmunedisorders; benign tumors; artheroscleric plaques; ocular angiogenicdiseases; rheumatoid arthritis; psoriasis; warts; allergic dermatitis;blistering disease; Katposi sarcoma; delayed wound healing;endometriosis; uterine bleeding; ovarian cysts; ovarianhyperstimulation; vasculogenesis; granulations; hypertrophic scars(keloids); nonunion fractures; scleroderma; trachoma; vascularadhesions; vascular malformations; DiGeorge syndrome; HHT; transplantarteriopathy; restinosis; obesity; myocardial angiogenesis; coronarycollaterals; cerebral collaterals; arteriovenous malformations; ischemiclimb angiogenesis; primary pulmonary hypertension; pulmonary edema;asthma; nasal polyps; inflammatory bowel disease; periodontal disease;ascites; peritoneal adhesions; Osler-Webber Syndrome; plaqueneovascularization; telangiectasia; hemophiliac joints; synovitis;osteomyelitis; osteophyte formation; angiofibroma; fibromusculardysplasia; wound granulation; Crohn's disease; and atherosclerosis. 25.The method of claim 24, wherein R₅ is represented by the followingformula:

wherein: R₉, for each occurrence, is independently a substituentselected from the group consisting of an optionally substituted alkyl,an optionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl,hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino, a haloalkyl, aheteroalkyl, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, or —S(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂; or two R₉ groups taken together with the carbon atoms towhich they are attached form a fused ring; and m is zero or an integerfrom 1 to
 7. 26. The method of claim 24, wherein R₅ is represented bythe following structural formula:

wherein: R₃₃ is a halo, lower alkyl, a lower alkoxy, a lower haloalkyl,a lower haloalkoxy, and lower alkyl sulfanyl; R₃₄ is H, a lower alkyl,or a lower alkylcarbonyl; and Ring B and Ring C are optionallysubstituted with one or more substituents.
 27. The method of claim 24,wherein R₅ is an optionally substituted indolyl, an optionallysubstituted benzoimidazolyl, an optionally substituted indazolyl, anoptionally substituted 3H-indazolyl, an optionally substitutedindolizinyl, an optionally substituted quinolinyl, an optionallysubstituted isoquinolinyl, an optionally substituted benzoxazolyl, anoptionally substituted benzo[1,3]dioxolyl, an optionally substitutedbenzofuryl, an optionally substituted benzothiazolyl, an optionallysubstituted benzo[d]isoxazolyl, an optionally substitutedbenzo[d]isothiazolyl, an optionally substitutedthiazolo[4,5-c]pyridinyl, an optionally substitutedthiazolo[5,4-c]pyridinyl, an optionally substitutedthiazolo[4,5-b]pyridinyl, an optionally substitutedthiazolo[5,4-b]pyridinyl, an optionally substitutedoxazolo[4,5-c]pyridinyl, an optionally substitutedoxazolo[5,4-c]pyridinyl, an optionally substitutedoxazolo[4,5-b]pyridinyl, an optionally substitutedoxazolo[5,4-b]pyridinyl,an optionally substituted imidazopyridinyl, anoptionally substituted benzothiadiazolyl, benzoxadiazolyl, an optionallysubstituted benzotriazolyl, an optionally substituted tetrahydroindolyl,an optionally substituted azaindolyl, an optionally substitutedquinazolinyl, an optionally substituted purinyl, an optionallysubstituted imidazo[4,5-a]pyridinyl, an optionally substitutedimidazo[1,2-a]pyridinyl, an optionally substituted3H-imidazo[4,5-b]pyridinyl, an optionally substituted1H-imidazo[4,5-b]pyridinyl, an optionally substituted1H-imidazo[4,5-c]pyridinyl, an optionally substituted3H-imidazo[4,5-c]pyridinyl, an optionally substituted pyridopyrdazinyl,and optionally substituted pyridopyrimidinyl, an optionally substitutedpyrrolo[2,3]pyrimidyl, an optionally substituted pyrazolo[3,4]pyrimidylan optionally substituted cyclopentaimidazolyl, an optionallysubstituted cyclopentatriazolyl, an optionally substitutedpyrrolopyrazolyl, an optionally substituted pyrroloimidazolyl, anoptionally substituted pyrrolotriazolyl, or an optionally substitutedbenzo(b)thienyl.
 28. The method of claim 24, wherein the compound isrepresented by the following structural formula:

or a tautomer or pharmaceutically acceptable salt thereof; wherein: R₆,for each occurrence, is independently an optionally substituted alkyl,an optionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteroaralkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, alkoxy, haloalkoxy,—NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇, —C(O)SR₇, —C(S)SR₇,—C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁,—C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇, —SC(O)R₇,—SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇, —OC(O)NR₁₀R₁₁,—OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁, —SC(NR₈)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇,—NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇, —NR₇C(NR₈)OR₇,—NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,—SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂; and n is zero of an integer from 1 to
 4. 29. A method ofblocking, occluding, or otherwise disrupting blood flow in a diseaseassociated with the neovasculature of a subject in need of suchtreatment, comprising administering to the subject an effective amountof a compound represented by the following structural formula:

or a tautomer or pharmaceutically acceptable salt thereof; wherein R₂ isa substituted phenyl, wherein the phenyl group is substituted with: i)one substituent selected from nitro, cyano, a haloalkoxy, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, anoptionally substituted heteraralkyl, hydroxylalkyl, alkoxyalkyl,guanadino, —O13 R₂₀, —C(O)R₇, —C(O)OR₂₀, —OC(O)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —S(O)_(p)NR₁₀R₁₁, —S(O)_(p)OR₇, —OP(O)(OR₇)₂, or—SP(O)(OR₇)₂; or ii) two to five substituents selected from the groupconsisting of an optionally substituted alkyl, an optionally substitutedalkenyl, an optionally substituted alkynyl, an optionally substitutedcycloalkyl, an optionally substituted cycloalkenyl, an optionallysubstituted heterocyclyl, an optionally substituted aryl, an optionallysubstituted heteroaryl, an optionally substituted aralkyl, an optionallysubstituted heteraralkyl, hydroxyalkyl, alkoxyalkyl, —F, —Br, —I, cyano,nitro, guanadino, a haloalkyl, a heteroalkyl, —NR₁₀R₁₁, —OR₇, —C(O)R₇,—C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇,—OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, —S(O)_(p)NR₁₀R₁₁,—OP(O)(OR₇)₂, or —SP(O)(OR₇)₂, —S(O)_(p)OR₇; wherein the disease isselected from infectious diseases;autoimmune disorders; benign tumors;artheroscleric plaques; ocular angiogenic diseases; rheumatoidarthritis; psoriasis; warts; allergic dermatitis; blistering disease;Karposi sarcoma; delayed wound healing; endometriosis; uterine bleeding;ovarian cysts; ovarian hyperstimulation; vasculogenesis; granulations;hypertrophic scars (keloids); nonunion fractures; scleroderma; trachoma;vascular adhesions; vascular malformations; DiGeorge syndrome; HHT;transplant arteriopathy; restinosis; obesity; myocardial angiogenesis;coronary collaterals; cerebral collaterals; arteriovenous malformations;ischemic limb angiogenesis; primary pulmonary hypertension; pulmonaryedema; asthma; nasal polyps; inflammatory bowel disease; periodontaldisease; ascites; peritoneal. adhesions; Osler-Webber Syndrome; plaqueneovascularization; telangiectasia; hemophiliac joints; synovitis;osteomyelitis; osteophyte formation: angiofibroma; fibromusculardysplasia; wound granulation; Crohn's disease; and atherosclerosis. 30.The method of claim 28, wherein the compound is represented by thefollowing structural formula:

or a tautomer or pharmaceutically acceptable salt thereof, wherein: R₂₅is an optionally substituted alkyl, an optionally substituted alkenyl,an optionally substituted alkynyl, an optionally substituted cycloalkyl,an optionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteroaralkyl, halo, cyano, nitro, guanadino, a haloalkyl, aheteroalkyl, alkoxy, haloalkoxy, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇,—C(S)R₇, —C(O)SR₇, —C(S)SR₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇,—OC(NR₈)OR₇, —SC(O)R₇, —SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇,—SC(S)OR₇, —OC(O)NR₁₀R₁₁, —OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₁,—SC(NR₈)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇,—NR₇C(NR₈)OR₇, —NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁,—SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇,—S(O)_(p)NR₁₀R₁₁, —SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁,—OP(O)(OR₇)₂, or —SP(O)(OR₇)₂; k is 1, 2, 3, or 4; and r is zero or aninteger from 1 to
 3. 31. The method of claim 30, wherein R₁, R₃ and R₂₅are each independently —OH, —SH, —NHR₇, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—OC(O)R₇, —SC(O)R₇, —OC(O)OR₇, —SC(O)OR₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—SS(O)_(p)R₇, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—OC(S)OR₇, —SC(S)OR₇, —OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —OC(NR₈)R₇,—SC(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —OP(O)(OR₇)₂ or —SP(O)(OR₇)₂. 32.The compound of claim 25, wherein R₁ and R₃ are each, independently,—OH, —SH, or —NHR₇.
 33. The method of claim 32, wherein the compound isrepresented by the following structural formula:

or a tautomer or pharmaceutically acceptable salt thereof; wherein R₆ isan optionally substituted alkyl, an optionally substituted alkenyl, anoptionally substituted alkynyl, cyano, halo, nitro, an optionallysubstituted cycloalkyl, haloalkyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteroaralkyl, —OR₇, —SR₇, —NR₁₀R₁₁, —OC(O)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇, —OC(O)OR₇, —SC(O)OR₇,—NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇, —NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇,—SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇, —OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁,—NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇, —SS(O)_(p)R₇, —NR₇S(O)_(p)R₇,—OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)NR₁₀R₁₁,—OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇, —OC(S)R₇, —SC(S)R₇,—NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇, —OC(S)NR₁₀R₁₁,—SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —NR₇C(NR₈)R₇,—OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁, —C(O)R₇, —C(O)OR₇, —C(O)NR₁₀R₁₁,—C(O)SR₇, —C(S)R₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(S)SR₇, —C(NR₈)OR₇,—C(NR₈)R₇, —C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —S(O)_(p)OR₇, —S(O)_(p)NR₁₀R₁₁,or —S(O)_(p)R₇.
 34. The method of claim 33, wherein: R₁ is —SH or —OH;R₃ and R₂₅ are —OH; R₆ is a lower alkyl, C3-C6 cycloalkyl, lower alkoxy,a lower alkyl sulfanyl, or —NR₁₀R₁₁; and R₉, for each occurrence, isindependently selected from the group consisting of —OH, —SH, halo, alower haloalkyl, cyano, a lower alkyl, a lower alkoxy, and a lower alkylsulfanyl.
 35. The method of claim 31, wherein the compound isrepresented by the following structural formula:

or a tautomer or pharmaceutically acceptable salt thereof; wherein R₆ isa C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, aC1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl, and R₁ and R₃ are each,independently, —OH, —SH, or —NHR₇.
 36. The method of claim 35, wherein:R₁ is —SH or —OH; R₃ and R₂₅ are —OH; R₆ is a lower alkyl, C3-C6cycloalkyl, lower alkoxy, a lower alkyl sulfanyl, or —NR₁₀R₁₁.
 37. Themethod of claim 24, wherein the compound is selected form the groupconsisting of:3-(2-Hydroxyphenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-[4-(2-methoxyethoxy)-naphthalen-1-yl]-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2-methyl-4-bromophenyl)-5-mercapto-triazole;3-(3,4-Dihydroxyphenyl)-4-(6-methoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(3,4-Dihydroxyphenyl)-4-(6-ethoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(3,4-Dihydroxyphenyl)-4-(6-propoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(5-methoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(3,4-Dihydroxyphenyl)-4-(6-isopropoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2,6-diethylphenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2-methyl-6-ethylphenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2,6-diisopropylphenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(1-ethyl-indol-4-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(3-methylphenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(4-methylphenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2-Chlorophenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(3-Chlorophenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(4-Chlorophenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2-methoxyphenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(3-methoxyphenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(3-fluorophenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2-ethylphenyl)-5-mercapto-triazole;3-(2-Hydroxy-4-fluorophenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2-Hydroxy-4-aminophenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2-methyl-4-butyl-phenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2,4-dimethyl-phenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2,6-dimethyl-phenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2,6-dimethyl-phenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(4-fluorophenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2-methylsulfanylphenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(naphthalene-2-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2,3-dimethylphenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2-methyl-4-fluorophenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(acenaphthalen-5-yl)-5-mercapto-triazole;3-(2-Hydroxy-4-methoxy-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2,3-dichlorophenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(5-methoxynaphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(pyren-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(quinolin-5-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(1,2,3,4-tetrahydronaphthalen-5-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(anthracen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(biphenyl-2-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-6-methyl-phenyl)-4-(naphthalene-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(4-pentyloxyphenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(4-octyloxyphenyl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(4-Chloronaphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(7-carboxymethoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(2-methyl-quinolin-4-yl)-5-mercapto-triazole;3-(3-Hydroxypyridin-4-yl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2-Hydroxy-4-acetylamino-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(1,2,3,4-tetrahydronaphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(3,5-dimethoxyphenyl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(2,3-dimethyl-1H-indol-4-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-3-propyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(4,6-Dihydroxy-1-ethyl-pyridin-3-yl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(4,6-Dihydroxy-1-methyl-pyridin-3-yl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(3,5-di-tert-butylphenyl)-5-mercapto-triazole;3-(2,6-Dihydroxy5-fluoro-pyridin-3-yl)4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-methyl-phenyl)-4-(naphthalene-1-yl)-5-mercapto-triazole;3-[2,4-Dihydroxy-phenyl]-4-(3-benzoylphenyl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(4-carboxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-[4-(N,N-dimethylcarbamoyl)-naphthalen-1-yl]-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(4-propoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(4-isopropoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(5-isopropoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(isoquinolin-5-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(5-propoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2-Hydroxy-4-methanesulfonamino-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-3,6-dimethyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-[7-(2-methoxyethoxy)-naphthalen-1-yl]-5-mercapto-triazole;3-(2,4-Dihydroxy-5-hexyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(4-methoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(6-methoxy-naphthalin-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-3-Chloro-5-ethyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(2,3-dimethyl-4-methoxy-phenyl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(7-isopropoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(7-ethoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(7-propoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2-Hydroxy-4-methoxymethyoxy-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-[2-Hydroxy-4-(2-hydroxy-ethoxy)-phenyl]-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(7-methoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(5-methoxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(4-hydroxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxyphenyl)-4-(1-isopropyl-indol-4-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-tert-butyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-propyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-3-methyl-5-ethyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-isobutyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(2,3-dimethoxy-phenyl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(2-methoxy-3-Chloro-phenyl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(indol-4-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-[1-(2-methoxyethoxy)-indol-4-yl]-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(naphthalen-1-yl)-5-hydroxy-triazole;3-(1-Oxo-3-hydroxy-pyridin-4-yl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,5-Dihydroxy-4-carboxy)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-indol-4-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-[1-(dimethyl-carbamoyl)-indol-4-yl]-5-mercapto-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-ethyl-benzoimidazol-4-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1,2,3-trimethyl-indol-5-yl)-5-mercapto-triazole;3-(2,5-Dihydroxy-4-hydroxymethyl-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2-Hydroxy-4-amino-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2-Hydroxy-4-acetylamino-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-3-Chloro-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(3-methoxy-phenyl)-5-hydroxy-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(naphthalen-1-yl)-5-hydroxy-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-indol-3-yl)-5-hydroxy-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-indol-4-yl)-5-amino-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(3-methoxy-phenyl)-5-amino-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(naphthalen-1-yl)-5-amino-triazole;3-(2-Hydroxy-5-ethyloxy-phenyl)-4-(naphthalen-1-yl)-5-hydroxy-triazole;3-(2-Hydroxy-5-isopropyl-phenyl)-4-(naphthalen-1-yl)-5-hydroxy-triazole;3-(2-Dihydroxy-phenyl)-4-(7-fluoro-naphthalen-1-yl)-5-hydroxy-triazole;3-(2,4-Dihydroxy-phenyl)-4-(2,3-difluorophenyl)-5-hydroxy-triazole;3-(2,4-Dihydroxy-phenyl)-4-[2-(1H-tetrazol-5-yl)-phenyl]-5-hydroxy-triazole;3-(2,4-Dihydroxy-phenyl)-4-(benzothiazol-4-yl)-5-hydroxy-triazole;3-(2,4-Dihydroxy-phenyl)-4-(9H-purin-6-yl)-5-hydroxy-triazole;3-(2,4-Dihydroxy-phenyl)-4-{4-[2-(moropholin-1-yl)-ethoxy]-phenyl}-5-hydroxy-triazole;3-(2,4-Dihydroxy-phenyl)-4-cyclopentyl-5-hydroxy-triazole;3-(2,4-Dihydroxy-phenyl)-4-phenyl-5-(sulfamoylamino)-triazole;3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(naphthalene-1-yl)-5-ureido-triazole;3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(2,3-difluorophenyl)-5-ureido-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-indol-4-yl)-5-ureido-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(quinolin-5-yl)-5-ureido-triazole;3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(naphthalene-1-yl)-5-carbamoyloxy-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(3-trifluoromethyl-phenyl)-5-carbamoyloxy-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-methyl-indol-4-yl)-5-carbamoyloxy-triazole;3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(8-methoxy-quinolin-5-yl)-5-carbamoyloxy-triazole;3-(2,4-Dihydroxy-5-isopropyl-phenyl)-4-(3-methyl-quinolin-5-yl)-5-carboxyamino-triazole;3-(2,4-Dihydroxy-phenyl)-4-(1-methyl-2-Chloro-indol-4-yl)-5-carbamoyloxy-triazole;3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-[3,5-di-(trifluoromethyl)-phenyl]-5-carbamoyloxy-triazole;3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(3-trifluoromethyl-phenyl)-5-(sulfamoylamino)-triazole;3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(naphthalene-1-yl)-5-(sulfamoylamino)-triazole;3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(1-isopropyl-benzoimidazol-4-yl)-5-(sulfamoylamino)-triazole;3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(3-isopropylphenyl)-5-(thiocarboxyamino)-triazole;3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(3-isopropyloxy-phenyl)-5-(sulfamoyloxy)-triazole;3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(naphthalene-1-yl)-5-(sulfamoyloxy)-triazole;3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(5-hydroxy-naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(naphthalen-1-ylmethyl)-5-mercapto-triazole;3-(2-Hydroxy-4-methoxyphenyl)-4-(naphthalen-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(biphenyl-3-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(2-methyl-5-hydroxymethyl-phenyl)-5-mercapto-triazole;3-(2,4-Dihydroxy-phenyl)-4-(1-dimethylcarbamoyl-indol-4-yl)-5-mercapto-triazole;3-(2,4,5-Trihydroxy-phenyl)-4-(naphthalene-1-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(2,3-dimethyl-indol-5-yl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(3-t-butyl-4-methoxy-phenyl)-5-mercapto-triazole;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-ethyl-1H-benzoimidazol-4-yl)-5-mercapto-triazole,HCl salt;3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-triazole;and3-(2,4-Dihydroxy-5-cyclopropyl-phenyl)-4-(naphthalene-1-yl)-5-mercapto-triazoleor a tautomer or pharmaceutically acceptable salt thereof.
 38. A methodof blocking, occluding, or otherwise disrupting blood flow in a diseaseassociated with neovasculature, comprising contacting the neovasculaturewith an effective amount of a compound represented by the followingstructural formula:

or a tautomer or pharmaceutically acceptable salt thereof, wherein: X₄₁is O, S, or NR₄₂; X₄₂ is CR₄₄ or N; Y₄₀ is N or CR₄₃; Y₄₁ is N or CR₄₅;Y₄₂, for each occurrence, is independently N, C or CR₄₆; Z is OH, SH, orNHR₇; R₄₁ is —H, —OH, —SH, an optionally substituted alkyl, anoptionally substituted alkenyl, an optionally substituted alkynyl, anoptionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl, halo,cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, an alkoxy orcycloalkoxy, a haloalkoxy, —NR₁₀R₁₁, —OR₇, —C(O)R₇, —C(O)OR₇, —C(S)R₇,—C(O)SR₇, —C(S)SR₇, —C(S)OR₇, —C(S)NR₁₀R₁₁, —C(NR₈)OR₇, —C(NR₈)R₇,—C(NR₈)NR₁₀R₁₁, —C(NR₈)SR₇, —OC(O)R₇, —OC(O)OR₇, —OC(S)OR₇, —OC(NR₈)OR₇,—SC(O)R₇, —SC(O)OR₇, —SC(NR₈)OR₇, —OC(S)R₇, —SC(S)R₇, —SC(S)OR₇,—OC(O)NR₁₀R₁₁, —OC(S)NR₁₀R₁₁, —OC(NR₈)NR₁₀R₁₁, —SC(O)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —NR₇C(S)R₇, —NR₇C(S)OR₇, —NR₇C(NR₈)R₇, —NR₇C(O)OR₇,—NR₇C(NR₈)OR₇, —NR₇C(O)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —NR₇C(NR₈)NR₁₀R₁₁,—SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —OS(O)_(p)OR₇, —OS(O)_(p)NR₁₀R₁₁,—S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, —NR₇S(O)_(p)NR₁₀R₁₁, —NR₇S(O)_(p)OR₇,—S(O)_(p)NR₁₀R₁₁, —SS(O)_(p)R₇, —SS(O)_(p)OR₇, —SS(O)_(p)NR₁₀R₁₁,—OP(O)(OR₇)₂, or —SP(O)(OR₇)₂; R₄₂ is —H, an optionally substitutedalkyl, an optionally substituted alkenyl, an optionally substitutedalkynyl, an optionally substituted cycloalkyl, an optionally substitutedcycloalkenyl, an optionally substituted heterocyclyl, an optionallysubstituted aryl, an optionally substituted heteroaryl, an optionallysubstituted aralkyl, an optionally substituted heteraralkyl,hydroxyalkyl, alkoxyalkyl, a haloalkyl, a heteroalkyl, —C(O)R₇,—(CH₂)_(m)C(O)OR₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —S(O)_(p)R₇,—S(O)_(p)OR₇, or —S(O)_(p)NR₁₀R₁₁; R₄₃ and R₄₄ are, independently, —H,—OH, an optionally substituted alkyl, an optionally substituted alkenyl,an optionally substituted alkynyl, an optionally substituted cycloalkyl,an optionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, an optionally substitutedheteraralkyl, hydroxyalkyl, alkoxyalkyl, halo, cyano, nitro, guanadino,a haloalkyl, a heteroalkyl, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁,—NR₈C(O)R₇, —SR₇, —S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇,—NR₈S(O)_(p)R₇, —S(O)_(p)NR₁₀R₁₁, or R₄₃ and R₄₄ taken together with thecarbon atoms to which they are attached form an optionally substitutedcycloalkenyl, an optionally substituted aryl, an optionally substitutedheterocyclyl, or an optionally substituted heteroaryl; R₄₅ is —H, —OH,—SH, —NR₇H, —OR₂₆, —SR₂₆, —NHR₂₆, —O(CH₂)_(m)OH, —O(CH₂)_(m)SH,—O(CH₂)_(m)NR₇H, —S(CH₂)_(m)SH, —S(CH₂)_(m)NR₇H, —OC(O)NR₁₀R₁₁,—SC(O)NR₁₀R₁₁, —NR₇C(O)NR₁₀R₁₁, —OC(O)R₇, —SC(O)R₇, —NR₇C(O)R₇,—OC(O)OR₇, —SC(O)OR₇, —NR₇C(O)OR₇, —OCH₂C(O)R₇, —SCH₂C(O)R₇,—NR₇CH₂C(O)R₇, —OCH₂C(O)OR₇, —SCH₂C(O)OR₇, —NR₇CH₂C(O)OR₇,—OCH₂C(O)NR₁₀R₁₁, —SCH₂C(O)NR₁₀R₁₁, —NR₇CH₂C(O)NR₁₀R₁₁, —OS(O)_(p)R₇,—SS(O)_(p)R₇, —NR₇S(O)_(p)R₇, —OS(O)_(p)NR₁₀R₁₁, —SS(O)_(p)NR₁₀R₁₁,—NR₇S(O)_(p)NR₁₀R₁₁, —OS(O)_(p)OR₇, —SS(O)_(p)OR₇, —NR₇S(O)_(p)OR₇,—OC(S)R₇, —SC(S)R₇, —NR₇C(S)R₇, —OC(S)OR₇, —SC(S)OR₇, —NR₇C(S)OR₇,—OC(S)NR₁₀R₁₁, —SC(S)NR₁₀R₁₁, —NR₇C(S)NR₁₀R₁₁, —OC(NR₈)R₇, —SC(NR₈)R₇,—NR₇C(NR₈)R₇, —OC(NR₈)OR₇, —SC(NR₈)OR₇, —NR₇C(NR₈)OR₇, —OC(NR₈)NR₁₀R₁₁,—SC(NR₈)NR₁₀R₁₁, or —NR₇C(NR₈)NR₁₀R₁₁; R₄₆, for each occurrence, isindependently, selected from the group consisting of H, an optionallysubstituted alkyl, an optionally substituted alkenyl, an optionallysubstituted alkynyl, an optionally substituted cycloalkyl, an optionallysubstituted cycloalkenyl, an optionally substituted heterocyclyl, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted aralkyl, an optionally substituted heteraralkyl,halo, cyano, nitro, guanadino, a haloalkyl, a heteroalkyl, —NR₁₀R₁₁,—OR₇, —C(O)R₇, —C(O)OR₇, —OC(O)R₇, —C(O)NR₁₀R₁₁, —NR₈C(O)R₇, —SR₇,—S(O)_(p)R₇, —OS(O)_(p)R₇, —S(O)_(p)OR₇, —NR₈S(O)_(p)R₇, or—S(O)_(p)NR₁₀R₁₁; R₇ and R₈, for each occurrence, are, independently,—H, an optionally substituted alkyl, an optionally substituted alkenyl,an optionally substituted alkynyl, an optionally substituted cycloalkyl,an optionally substituted cycloalkenyl, an optionally substitutedheterocyclyl, an optionally substituted aryl, an optionally substitutedheteroaryl, an optionally substituted aralkyl, or an optionallysubstituted heteraralkyl; R₁₀ and R₁₁, for each occurrence, areindependently —H, an optionally substituted alkyl, an optionallysubstituted alkenyl, an optionally substituted alkynyl, an optionallysubstituted cycloalkyl, an optionally substituted cycloalkenyl, anoptionally substituted heterocyclyl, an optionally substituted aryl, anoptionally substituted heteroaryl, an optionally substituted aralkyl, oran optionally substituted heteraralkyl; or R₁₀ and R₁₁, taken togetherwith the nitrogen to which they are attached, form an optionallysubstituted heterocyclyl or an optionally substituted heteroaryl; R₂₆,for each occurrence is, is independently, a lower alkyl; p, for eachoccurrence, is, independently, 1 or 2; and m, for each occurrence, isindependently, 1, 2, 3, or 4, wherein the neovasculature is in a subjectin need of treatment to block, occlude or otherwise disrupt blood flowin the neovasculature; wherein the disease is selected rom infectiousdiseases; autoimmune disorders; benign tumors; artheroscleric plaques;Ocular angiogenic diseases; rheumatoid arthritis; psoriasis; warts;allergic dermatitis; blistering disease; Karposi sarcoma; delayed woundhealing; endometriosis; Uterine bleeding; ovarian cysts; ovarianhyperstimulation; vasculogenesis; granulations; hypertrophic scars.(keloids); nonunion fractures; scleroderma: trachoma; vascularadhesions; vascular malformations; DiGeorge syndrome; HHT; transplantarteriopathy; restinosis; obesity; myocardial angiogenesis; coronarycollaterals; cerebral collaterals; arteriovenous. malformations;ischemic limb angiogenesis; primary pulmonary hypertension; pulmonaryedema; asthma; nasal polyps; inflammatory bowel disease; periodontaldisease; ascites; peritoneal adhesions; Osler-Webber Syndrome; plaqueneovascularization; telangiectasia; hemophiliac joints; synovitis;osteomyelitis; osteophyte formation; angiofibroma; fibromusculardysplasia; wound granulation; Crohn's disease; and atherosclerosis. 39.The method of claim 38, wherein X₄₁ is NR₄₂ and X₄₂ is CR₄₄.
 40. Themethod of claim 38, wherein X₄₁ is NR₄₂, and R₄₂ is selected from thegroup consisting of —H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl,n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, —C(O)OH,—(CH₂)_(m)C(O)OH, —CH₂OCH₃, —CH₂CH₂OCH₃, and —C(O)N(CH₃)₂.
 41. Themethod of claim 38, wherein R₄₃ and R₄₄ are, independently, selectedfrom the group consisting of —H, methyl, ethyl, propyl, isopropyl,cyclopropyl, methoxy, ethoxy, propoxy, and cyclopropoxy; and Z is —OH or—SH.
 42. The method of claim 38, wherein the compound is selected fromthe group consisting of:3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2-methyl-7-methoxy-benzofuran-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(benzofuran-5-yl)-5-mercapto-[1,2,4]triazole,and3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2-methyl-1,3-benzoxaz-5-yl)-5-mercapto-[1,2,4]triazole;or a tautomer or pharmaceutically acceptable salt thereof.
 43. Themethod of claim 38, wherein the compound is represented by the followingstructural formula:

or a tautomer or pharmaceutically acceptable salt thereof, wherein Z₁ is—OH or —SH.
 44. The method of claim 43, wherein X₄₂ is CR₄₄, and R₄₃ andR₄₄ are, independently, selected from the group consisting of —H,methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy,and cyclopropoxy.
 45. The method of claim 43, wherein: X₄₅ is CR₅₄ or N;R₅₆ is selected from the group consisting of —H, methyl, ethyl,isopropyl, and cyclopropyl; R₅₂ is selected from the group consisting of—H, methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl,—(CH₂)₂OCH₃, —CH₂C(O)OH, and —C(O)N(CH₃)₂; R₅₃ and R₅₄ are each,independently, —H, methyl, ethyl, or isopropyl; or R₅₃ and R₅₄ takentogether with the carbon atoms to which they are attached form a phenyl,cyclohexenyl, or cyclooctenyl ring; and R₅₅ is selected from the groupconsisting of —H, —OH, —OCH₃, and —OCH₂CH₃.
 46. The method of claim 38,wherein the compound is selected from the group consisting of:3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-hydroxy-[1,2,4]triazole,3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-isopropyl-indol-4-yl)-5-hydroxy-[1,2,4]triazole;3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indazol-5-yl)-5-mercapto-[1,2,4]triazole;3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-indazol-6-yl)-5-mercapto-[1,2,4]triazole;3-(2,4-dihydroxyphenyl)-4-(1-ethyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxyphenyl)-4-(1-isopropyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxyphenyl)-4-(indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxyphenyl)-4-(1-methoxyethyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,3(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxyphenyl)-4-(1-dimethylcarbamoyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-propyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,2,3-trimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-acetyl-2,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-propyl-2,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-methyl-tetrahydrocarbozol-7-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-methyl-cyclononan[a]indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-n-butyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-n-pentyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-n-hexyl-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1-(1-methylcyclopropyl)-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1,2,3-trimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazoledisodium salt,3-(2,4-dihydroxy-5-tert-butyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1-propyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-methyl-3-ethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-isopropyl-7-methoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-methyl-3-isopropyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(N-ethyl-carbozol-7-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-7-hydroxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-isopropyl-7-ethoxy-indol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,2-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-44N-methyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1,3-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-cyclopropyl-phenyl)-4-(1-methyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1H-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1,2-dimethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-ethyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-propyl-indol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-ethyl-benzimidazol-4-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-ethyl-benzimidazol-4-yl)-5-mercapto-[1,2,4]triazole HCL salt,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(2-methyl-3-ethyl-benzimidazol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-ethyl-phenyl)-4-(1-ethyl-2-methyl-benzimidazol-5-yl)-5-mercapto-[1,2,4]triazole,3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(1-methyl-2-trifluoromethyl-benzimidazol-5-yl)-5-mercapto-[1,2,4]triazole;and3-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(N-methyl-indol-5-yl)-5-mercapto-[1,2,4]triazole;or tautomers or pharmaceutically acceptable salts thereof.